Biology subjects

Deng, T.

Publications and source records attributed to Deng, T..

32 records · Page 2Linked to original sources

bioRxiv2021

Reversion of antibiotic resistance in drug-resistant bacteria using non-steroidal anti-inflammatory drug benzydamine

Antimicrobial resistance has been a growing concern that gradually undermines our tradition treatment regimen. The fact that few antibacterial drugs with new scaffolds or targets have been approved in the past two decades aggravates this crisis. Repurposing previously approved drugs as potent antibiotic adjuvants offers a cost-effective strategy to mitigate the development of resistance and tackle the increasing infections by multidrug-resistant (MDR) bacteria. Herein, we found that benzydamine, a widely used non-steroidal anti-inflammatory drug in clinic, remarkably potentiated broad-spectrum antibiotic-tetracyclines activity against a panel of clinical important resistant pathogens, including MRSA, VRE, MCRPEC and tet(X)-positive Gram-negative bacteria. Further mechanistically experiments showed that benzydamine dissipated membrane potential ({Delta}{Psi}) in both Gram-positive and negative bacteria, which in turn upregulated the transmembrane proton gradient ({Delta}pH) and promoted the uptake of tetracyclines. Additionally, benzydamine exacerbated the oxidative stress by triggering the production of ROS and suppressing GAD system-mediated oxidative defensive. This mode of action explains the great bactericidal activity of the doxycycline-benzydamine combination against different metabolic states of bacteria including persister cells. As a proof-of-concept, the in vivo efficacy of this combination therapy was evidenced in multiple animal infection models. These findings revealed that benzydamine is a promising tetracycline antibiotics adjuvant and has the potential to address life-threatening infections by MDR bacteria.

microbiology↗

bioRxiv2021

H3K27 Acetylated Nucleosomes Facilitate HMGN Protein Localization at Regulatory Sites to Modulate The Interaction of Transcription Factors with Chromatin

Nucleosomes containing acetylated H3K27 are a major epigenetic mark of active chromatin and identify cell-type specific chromatin regulatory regions which serve as binding sites for transcription factors. Here we show that the ubiquitous nucleosome binding proteins HMGN1 and HMGN2 bind preferentially to H3K27ac nucleosomes at cell-type specific chromatin regulatory regions. HMGNs bind directly to the acetylated nucleosome; the H3K27ac residue and linker DNA facilitate the preferential binding of HMGNs to the modified nucleosomes. Loss of HMGNs increases the levels of H3K27me3 and the histone H1 occupancy at enhancers and promoters and alters the interaction of transcription factors with chromatin. These experiments indicate that the H3K27ac epigenetic mark affects the interaction of architectural protein with chromatin regulatory sites and provide insights into the molecular mechanism whereby ubiquitous chromatin binding proteins, which bind to chromatin without DNA sequence specificity, localize to regulatory chromatin and modulate cell-type specific gene expression.

molecular biology↗

bioRxiv2021

Insights into the drivers of radiating diversification in biodiversity hotspots using Saussurea (Asteraceae) as a case

O_LIThe Qinghai-Tibet Plateau (QTP) encompasses areas with a remarkably high degree of biodiversity, harboring exceptional species-rich radiations. How these radiations formed by interacting with geology, climate and ecology remains seldom examined. C_LIO_LIWe investigate the roles of abiotic (environmental) and biotic (species-intrinsic) factors in driving radiating diversification of Saussurea (Asteraceae) by deploying a number of time-dependent, paleoenvironment-dependent and trait-dependent models, as well as ecological distribution data. C_LIO_LIWe show that three main clades of Saussurea begin to diversify in the Miocene almost simultaneously, with increasing diversification rates toward the present and negative dependence to paleotemperature. Acceleration in diversification rates are correlated with adaptive traits, as well climate lability, niche breadth and species range. C_LIO_LIWe conclude that fluctuation of paleoclimate along with complex QTP environments provided opportunities for increased diversification rates of Saussurea with diverse adaptive traits, highlighting the importance of combinations of clade-specific traits and ecological niches in driving rapid radiation. C_LI

evolutionary biology↗

bioRxiv2020

Piezo2 mediates ultrasonic hearing via cochlear outer hair cells in mice

Ultrasonic hearing is exploited for hunting and navigation as in echolocation by microbats and bottleneck dolphins, and for social communication like ultrasonic vocalization by mice and rats. However, the molecular and cellular basis for ultrasonic hearing is not known yet. Here we show that knockout of the mechanosensitive ion channel PIEZO2 in cochlea disrupts the ultrasonic hearing but not the low-frequency hearing in mice, as shown by audiometry and acoustically-associative freezing behavior. Deletion of Piezo2 in the outer hair cells specifically abolishes the associative learning of the mice upon hearing the ultrasonic frequency. Ex vivo cochlear Ca2+ imaging revealed that the ultrasonic transduction requires both PIEZO2 and the hair-cell mechanotransduction channel. Together, our study demonstrates that the outer hair cells are the effector cells with PIEZO2 as an essential molecule for ultrasonic hearing in mice. Significance StatementSome animals have evolved an incredible ability for vocalizing and hearing ultrasonic frequencies that is inaudible for humans (> 20 kHz). For many years, it has been considered that animals hear ultrasonic frequencies with their cochlear hair cells, using the identical set of mechanotransduction molecules in the hair bundles for hearing audible frequencies. Here, we show that the mice lacking the mechanosensitive ion channel PIEZO2 hardly hear ultrasonic frequencies, while can still be sensitive to audible frequencies. Thus, animals may use a partially different mechanism for sensing physiological ultrasound.

neuroscience↗

bioRxiv2020

GTPBP1 resolves paused ribosomes to maintain neuronal homeostasis

Ribosome-associated quality control pathways respond to defects in translational elongation to recycle arrested ribosomes and degrade aberrant polypeptides and mRNAs. Loss of an individual tRNA gene leads to ribosomal pausing that is resolved by the translational GTPase GTPBP2, and in its absence causes neuron death. Here we show that loss of the homologous protein GTPBP1 during tRNA deficiency in the mouse brain also leads to codon-specific ribosome pausing and neurodegeneration, suggesting that these non-redundant translational GTPases function in the same pathway to mitigate ribosome pausing. Ribosome stalling in the mutant brain led to activation of the integrated stress response (ISR) mediated by GCN2 and decreased mTORC1 signaling. However, in contrast to the ISR, which enhanced neuron survival, reduced mTORC1 signaling increased neuronal death. Our data demonstrate that GTPBP1 functions as an important quality control mechanism during translation elongation and suggest that translational signaling pathways intricately interact to regulate neuronal homeostasis during defective translation elongation.

neuroscience↗

bioRxiv2020

The genome assembly and annotation of Magnolia biondii Pamp., a phylogenetically, economically, and medicinally important ornamental tree species

Magnolia biondii Pamp. (Magnoliaceae, magnoliids) is a phylogenetically, economically, and medicinally important ornamental tree species widely grown and cultivated in the north-temperate regions of China. Contributing a genome sequence for M. biondii will help resolve phylogenetic uncertainty of magnoliids and further understand individual trait evolution in Magnolia. We assembled a chromosome-level reference genome of M. biondii using ~67, ~175, and ~154 Gb of raw DNA sequences generated by Pacific Biosciences Single-molecule Real-time sequencing, 10X genomics Chromium, and Hi-C scaffolding strategies, respectively. The final genome assembly was 2.22 Gb with a contig N50 of 269.11 Kb and a BUSCO complete gene ratio of 91.90%. About 89.17% of the genome length was organized to 19 chromosomes, resulting in a scaffold N50 of 92.86 Mb. The genome contained 48,319 protein-coding genes, accounting for 22.97% of the genome length, in contrast to 66.48% of the genome length for the repetitive elements. We confirmed a Magnoliaceae specific WGD event that might have probably occurred shortly after the split of Magnoliaceae and Annonaceae. Functional enrichment of the Magnolia specific and expanded gene families highlighted genes involved in biosynthesis of secondary metabolites, plant-pathogen interaction, and response to stimulus, which may improve ecological fitness and biological adaptability of the lineage. Phylogenomic analyses recovered a sister relationship of magnoliids and Chloranthaceae, which are sister to a clade comprising monocots and eudicots. The genome sequence of M. biondii could empower trait improvement, germplasm conservation, and evolutionary studies on rapid radiation of early angiosperms.

plant biology↗

bioRxiv2020

A preliminary study on the reproductive toxicity of GS-5734 on male mice

BackgroundGS-5734 as a novel and promising medicine for COVID-2019, its biological impact on the mammalian reproductive system has not been systematically studied. The aim of this study was to evaluate the effects of GS-5734 on sperm parameters and spermatogenesis in mice. Materials and MethodsIn this study, GS-5734 was synthesized according to the report. 28 adult male mice were randomly segregated into four groups (n=7 for each group). The group 1 was set as the control group, the group 1, 2, 3 and 4 were administered with GS-5734 at a daily dose of 0, 10, 50, 150 g/mouse respectively, by intraperitoneal injection for 10 days. On the 7th day after the last injection, the testes and cauda epididymides were collected for HE staining and sperm concentration, motility, morphology analysis. ResultsThe results indicated that after treated with GS-5734, the total sperm count and motile sperm rate showed downward trends, the abnormal sperm rate showed an increasing trend. As compared with the control group, GS-5734 at a daily dose of 150 g/mouse caused a significant decrease in sperm concentration and motility, and a significant increased of abnormal sperm rate; the 50 g/mouse drug treatment lead to a significant decrease in sperm motility and an increase in abnormal sperm rate. The HE staining of testicular and epididymal tissues showed that the spermatogenesis of mice was significantly deteriorated with the increasing dosage of GS-5734, especially in the 150 g/mouse group. ConclusionOur findings suggest that a high dosage of GS-5734 may induce testicular toxicity and result in deterioration of sperm parameters in mice. More investigation on the reproductive toxicity of GS-5734 is required.

developmental biology↗

bioRxiv2020

Plastome phylogenomic study of Gentianeae (Gentianaceae): widespread gene tree discordance and its association with evolutionary rate heterogeneity of plastid genes

BackgroundPlastome-scale data have been prevalent in reconstructing the plant Tree of Life. However, phylogenomic studies currently based on plastomes rely primarily on maximum likelihood (ML) inference of concatenated alignments of plastid genes, and thus phylogenetic discordance produced by individual plastid genes has generally been ignored. Moreover, structural and functional characteristics of plastomes indicate that plastid genes may not evolve as a single locus and are experiencing different evolutionary forces, yet the genetic characteristics of plastid genes within a lineage remain poorly studied. ResultsWe sequenced and annotated ten plastome sequences of Gentianeae. Phylogenomic analyses yielded robust relationships among genera within Gentianeae. We detected great variation of gene tree topologies and revealed more than half of the genes, including one (atpB) of the three widely used plastid markers (rbcL, atpB and matK) in phylogenetic inference of Gentianeae, are likely contributing to phylogenetic ambiguity of Gentianeae. Estimation of nucleotide substitution rates showed extensive rate heterogeneity among different plastid genes and among different functional groups of genes. Comparative analysis suggested that the ribosomal protein (RPL and RPS) genes and the RNA polymerase (RPO) genes have higher substitution rates and genetic variations in Gentianeae. Our study revealed that just one (matK) of the three (matK, ndhB and rbcL) widely used markers show high phylogenetic informativeness (PI) value. Due to the high PI and lowest gene-tree discordance, rpoC2 is advocated as a promising plastid DNA barcode for taxonomic studies of Gentianeae. Furthermore, our analyses revealed a positive correlation of evolutionary rates with genetic variation of plastid genes, but a negative correlation with gene-tree discordance under purifying selection. ConclusionsOverall, our results demonstrate the heterogeneity of nucleotide substitution rates and genetic characteristics among plastid genes providing new insights into plastome evolution, while highlighting the necessity of considering gene-tree discordance into phylogenomic studies based on plastome-scale data.

evolutionary biology↗

bioRxiv2020

Genome wide sequencing provides evidence of adaptation to heterogeneous environments for the ancient relictual Circaeaster agrestis (Circaeasteraceae, Ranunculales)

O_LIInvestigating the interaction between environmental heterogeneity and local adaptation is critical to understand the evolutionary history of a species, providing the premise for studying the response of organisms to rapid climate change. However, for most species how exactly the spatial heterogeneity promotes population divergence and how genomic variations contribute to adaptive evolution remain poorly understood. C_LIO_LIWe examine the contributions of geographical and environmental variables to population divergence of the relictual, alpine herb Circaeaster agrestis, as well as genetic basis of local adaptation using RAD-seq and plastome data. C_LIO_LIWe detected significant genetic structure with an extraordinary disequilibrium of genetic diversity among regions, and signals of isolation-by-distance along with isolation-by-resistance. The populations were estimated to begin diverging in the late Miocene, along with a possible ancestral distribution of the Hengduan Mountains and adjacent regions. Both environmental gradient and redundancy analyses revealed significant association between genetic variation and temperature variables. Genome-environment association analyses identified 16 putatively adaptive loci related to biotic and abiotic stress resistance. C_LIO_LIOur genome wide data provide new insights into the important role of environmental heterogeneity in shaping genetic structure, and access the footprints of local adaptation in an ancient relictual species, informing conservation efforts. C_LI

evolutionary biology↗

bioRxiv2020

The draft genome of the endangered, relictual plant Kingdonia uniflora (Circaeasteraceae, Ranunculales) reveals potential mechanisms and perils of evolutionary specialization

Kingdonia uniflora, an alpine herb, has an extremely narrow distribution and represents a model for studying evolutionary mechanisms of species that have adapted to undisturbed environments for evolutionary long periods of time. We assembled a 1,004.7-Mb draft genome (encoding 43,301 genes) and investigated the evolutionary history of K. uniflora, along with mechanisms related to its endangered status. Phylogenomic analyses based on 497 single copy genes confirmed the sister relationship between K. uniflora and Circaeaster agrestis, which were estimated to have diverged around 52 Mya. Proliferation of LTR retrotransposons in K. uniflora is estimated to occur around 2.7 Mya, coinciding with one recent uplift of the Hengduan Mountains between the late Miocene and late Pliocene. Across 12 species of monocots, early-diverging eudicots and core eudicots, K. uniflora showed significant overrepresentation in gene families associated with DNA repair and underrepresentation in gene families associated with stress response. Most of the plastid ndh genes were found to be lost not only in the plastome but also in the nuclear genome of K. uniflora. During the evolutionary process, the overrepresentation of gene families involved in DNA repair could help asexual K. uniflora reduce the accumulation of deleterious mutations, while at the same time, reducing genetic diversity which is important in responding to environment fluctuations. The underrepresentation of gene families related to stress response and functional loss of ndh genes could be due to lack or loss of ability to respond to environmental changes caused by long-term adaptation to a relatively stable ecological environment.

genomics↗

bioRxiv2019

A Versatile Polypharmacology Platform Promotes Cytoprotection and Viability of Human Pluripotent and Differentiated Cells

Clinical translation of human pluripotent stem cells (hPSCs) requires advanced strategies that ensure safe and robust long-term growth and functional differentiation. Pluripotent cells are capable of extensive self-renewal, yet remain highly sensitive to environmental perturbations in vitro, posing challenges to their therapeutic use. Here, we deployed innovative high-throughput screening strategies to identify a small molecule cocktail that dramatically improves viability of hPSCs and their differentiated progeny. We discovered that the combination of Chroman 1, Emricasan, Polyamines, and Trans-ISRIB (CEPT) enhanced cell survival of genetically stable hPSCs by simultaneously blocking several stress mechanisms that otherwise compromise cell structure and function. In proof-of-principle experiments we then demonstrated the strong improvements that CEPT provided for several key applications in stem cell research, including routine cell passaging, cryopreservation of pluripotent and differentiated cells, embryoid body and organoid formation, single-cell cloning, genome editing, and new iPSC line generation. Thus, CEPT represents a unique polypharmacology strategy for comprehensive cytoprotection, providing a new rationale for efficient and safe utilization of hPSCs. Conferring cell fitness by multi-target drug combinations may become a common approach in cryobiology, drug development, and regenerative medicine.

cell biology↗

bioRxiv2019

The C. elegans homolog of the Evi1 proto-oncogene, egl-43, coordinates G1 cell cycle arrest with pro-invasive gene expression during anchor cell invasion

Cell invasion allows cells to migrate across compartment boundaries formed by basement membranes. Aberrant cell invasion is a first step during the formation of metastases by malignant cancer cells.\n\nAnchor cell (AC) invasion in C. elegans is an excellent in vivo model to study the regulation of cell invasion during development. Here, we have examined the function of egl-43, the homolog of the human Evi1 proto-oncogene (also called MECOM), in the invading AC. egl-43 plays a dual role in this process, firstly by imposing a G1 cell cycle arrest to prevent AC proliferation, and secondly, by activating pro-invasive gene expression. We have identified the AP-1 transcription factor fos-1 and the Notch homolog lin-12 as critical egl-43 targets. A positive feedback loop between fos-1 and egl-43 induces pro-invasive gene expression in the AC, while repression of lin-12 Notch expression by egl-43 ensures the G1 cell cycle arrest necessary for invasion. Reducing lin-12 levels in egl-43 depleted animals restored the G1 arrest, while hyperactivation of lin-12 signaling in the differentiated AC was sufficient to induce proliferation.\n\nTaken together, our data have identified egl-43 Evi1 as a critical factor coordinating cell invasion with cell cycle arrest.\n\nAuthor summaryCells invasion is a fundamental biological process that allows cells to cross compartment boundaries and migrate to new locations. Aberrant cell invasion is a first step during the formation of metastases by malignant cancer cells.\n\nWe have investigated how a specialized cell in the Nematode C. elegans, the so-called anchor cell, can invade into an adjacent epithelium. Our work has identified an oncogenic transcription factor that controls the expression of specific target genes necessary for cell invasion, and at the same time inhibits the proliferation of the invading anchor cell.\n\nThese findings shed light on the mechanisms, by which cells decide whether to proliferate or invade.

developmental biology↗

bioRxiv2019

Genome-wide analysis reveals genetic diversity, linkage disequilibrium, and selection for milk traits in Chinese buffalo breeds

Water buffalo holds the tremendous potential of milk and meat that widespread throughout central and southern China. However, characterization of the population genetics of Chinese buffalo is poorly understood. Using Axiom(R) buffalo genotyping array, we performed the genetic diversity, linkage disequilibrium (LD) pattern and signature of selection in the 176 Chinese buffaloes from thirteen breeds. A total of 35,547 SNPs passed quality control and were used for further analyses. Population genetic analysis revealed a clear separation between the swamp and river types. Ten Chinese indigenous breeds clustered into the swamp group, Murrah and Nili-Ravi breeds were the river group, and the crossbred breed was closer to the river group. Genetic diversity analysis showed that the swamp group had a lower average expected heterozygosities compared to the river group. LD decay distance was much shorter in the swamp group compared with the river group with [Formula] value of approximately 50 Kb. Analysis of runs of homozygosity indicated that extensive remote and recent inbreeding activity was respectively found within swamp and river groups. Moreover, a total of 12 genomic regions under selection were detected between river and swamp groups. Further, 12 QTL regions were found associated with buffalo milk production traits. Some candidate genes within these QTLs were predicted to be involved in the cell structure and function, suggesting that these genes might play vital roles in the buffalo milk performance. Our data contribute to our understanding of the characterization of population genetics in Chinese buffaloes, which in turn may be utilized in buffalo breeding programs.\n\nAuthor SummaryIdentifying the causal genes or markers associated with important economic traits in livestock is critical to increasing the production level on the species. However, current understanding of the genetic basis for milk production traits in buffalo is limited. Here, we confirmed the divergent evolution, distinct population structure, and LD extent among Chinese buffalo breeds. We also identified 12 QTL regions associated with milk production traits in buffaloes using the selective sweeps and haplotype analysis. Further, a total of 7 genes involved in the cell structure and function were predicted within the identified QTLs. These findings suggested that these genes can serve as the candidate genes associated with buffalo milk production, which hold a vital role in the milk trait improvement of dairy buffalo industry.

genetics↗

bioRxiv2017

Deubiquitylation and stabilization of p21 by USP11 is critical for cell cycle progression and DNA damage responses

p21WAF1/CIP1 is a broad-acting cyclin-dependent kinase inhibitor. Its stability is essential for proper cell cycle progression and cell fate decision. Ubiquitylation by the multiple E3 ubiquitin ligases complex is the major regulatory mechanism of p21, which induces p21 degradation. However, it is unclear whether ubiquitylated p21 can be recycled. In this study, we report USP11 as a deubiquitylase of p21. In the nucleus, USP11 binds to p21, catalyzes the removal of polyubiquitin chains conjugated onto p21 and stabilizes p21 protein. As a result, USP11 reverses p21 polyubiquitylation and degradation mediated by SCFSKP2, CRL4CDT2 and APC/CCDT20 in a cell cycle-independent manner. Loss of USP11 causes the destabilization of p21 and induces the G1/S transition in unperturbed cells. Furthermore, p21 accumulation mediated by DNA damage is completely abolished in cells depleted of USP11, which results in abrogation of the G2 checkpoint and induction of apoptosis. Functionally, USP11-mediated stabilization of p21 inhibits cell proliferation and tumorigenesis in vivo. These findings reveal an important mechanism by which p21 can be stabilized by direct deubiquitylation and pinpoint a crucial role of the USP11-p21 axis in regulating cell cycle progression and DNA damage responses.

cell biology↗