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Yang, M.

Publications and source records attributed to Yang, M..

At least 325 records · Page 18Linked to original sources
bioRxiv2020

Lipidomic analysis of roseobacters of the pelagic RCA cluster and their response to phosphorus limitation

The marine roseobacter-clade Affiliated cluster (RCA) represents one of the most abundant groups of bacterioplankton in the global oceans, particularly in temperate and sub-polar regions. They play a key role in the biogeochemical cycling of various elements and are important players in oceanic climate-active trace gas metabolism. In contrast to copiotrophic roseobacter counterparts such as Ruegeria pomeroyi DSS-3 and Phaeobacter sp. MED193, RCA bacteria are truly pelagic and have smaller genomes. We have previously shown that RCA bacteria do not appear to encode the PlcP-mediated lipid remodelling pathway, whereby marine heterotrophic bacteria remodel their membrane lipid composition in response to phosphorus (P) stress by substituting membrane glycerophospholipids with alternative glycolipids or betaine lipids. In this study, we report lipidomic analysis of six RCA isolates. In addition to the commonly found glycerophospholipids such as phosphatidylglycerol and phosphatidylethanolamine, RCA bacteria synthesise a relatively uncommon phospholipid, acylphosphatidylglycerol, which is not found in copiotrophic roseobacters. Instead, like the abundant SAR11 clade, RCA bacteria upregulate ornithine lipid biosynthesis in response to P stress, suggesting a key role of this aminolipid in the adaptation of marine heterotrophs to oceanic nutrient limitation.

microbiology↗
bioRxiv2020

LncRNA H19X is required for placenta development and angiogenesis through regulating a noncoding RNA regulatory network

H19X is a lncRNA specifically expressed in the placenta, whose expression is induced by hypoxia. H19X overexpression promoted trophoblast proliferation and invasion, while its knockdown or knockout inhibited trophoblast proliferation and invasion. Mechanistically, we demonstrated that reciprocal regulation exists with miR-424/miR-503 in the control of genes related to placental development and angiogenesis, including VEGF and VEGFR2. H19X inhibited ubiquitination of PIWIL1, thereby maintaining its stability and homeostatic expression of piRNAs. PIWIL1 overexpression rescued the defects of cell behavior caused by H19X KO. H19X deletion led to compromised HIF-1A/HIF-2A expression, which was correlated with the dysregulation of downstream genes under hypoxic conditions. CRISPR/Cas-9 knockout of H19X in animals led to defective placenta differentiation and compromised embryo development under hypoxic conditions. Western blotting showed reduced expression levels of PIWIL1 as well as angiogenesis marker genes, including VEGF and VEGFR2, in H19X KO mice. Thus, this study provides evidence of an unexpected link among lncRNA, miRNA, PIWIL1-related piRNA, and angiogenesis in placentation, the dysregulation of which leads to poor placental development and embryo loss under hypoxic conditions.

developmental biology↗
bioRxiv2020

Structural Basis of Complex Formation Between Mitochondrial Anion Channel VDAC1 and Hexokinase-II

Complex formation between hexokinase-II (HKII) and the mitochondrial channel VDAC1 plays a crucial role in regulating cell growth and survival; however, structural details of this complex remain elusive. We hypothesize that a conserved, hydrophobic helix (H-anchor) of HKII first inserts into the outer membrane of mitochondria (OMM) and then interacts with VDAC1 on the cytosolic leaflet of OMM to form a binary complex. To systematically investigate this process, we adopted a hybrid approach: 1) the membrane binding of HKII was first described with molecular dynamics (MD) simulations employing a membrane mimetic model with enhanced lipid diffusion, then 2) the resulting membrane-bound HKII was used to form complex with VDAC1 in millisecond-scale Brownian dynamics (BD) simulations. We show that H-anchor inserts its first 10 residues into the membrane, substantiating previous experimental findings. The insertion depth of the H-anchor was used to derive positional restraints in subsequent BD simulations to preserve the membrane-bound pose of HKII during the formation of the HKII/VDAC1 binary complex. Multiple BD-derived structural models were further refined with MD simulations, resulting in one stable complex. A major feature in the complex is the partial (not complete) blockade of VDAC1s permeation pathway by HKII, a result supported by our comparative electrophysiological measurements of the channel in the presence and absence of HKII. Additionally, we showed how VDAC1 phosphorylation disrupts HKII binding, a feature that is verified by our electrophysiology recordings and have implications in mitochondria-mediated cell death.

biophysics↗
bioRxiv2020

Transcriptome Profiling of different types of human respiratory tract cells infected by SARS-CoV-2 Highlight an unique Role for Inflammatory and Interferon Response

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) at the end of 2019 has caused a large global outbreak and now become a major public health issue. Lack of data underlying how the human host interacts with SARS-CoV-2 virus. In the current study, We performed Venn-analysis, Gene ontology (GO), KEGG pathway analysis and Protein-protein interaction analysis of whole transcriptome studies with the aim of clarifying the genes and pathways potentially altered during human respiratory tract cells infected with SARS-CoV-2. We selected four studies through a systematic search of the Gene Expression Omnibus (GEO) database or published article about SARS-CoV-2 infection in different types of respiratory tract cells. We found 36 overlapping upregulated genes among different types of cells after viral infection. Further functional enrichment analysis revealed these DEGs are most likely involved in biological processes related to inflammatory response and response to cytokine, cell component related to extracellular space and I-kappaB/NF-kappaB complex, molecular function related to protein binding and cytokine activity. KEGG pathways analysis highlighted altered conical and casual pathways related to TNF, NF-kappa B, Cytokine-cytokine receptor interaction and IL17 signaling pathways during SARS-CoV-2 infection with CXCL1, CXCL2, CXCL3, CXCL8, CXCL10, IL32, CX3CL1, CCL20, IRF1, NFKB2 and NFKB1A up-regulated which may explain the inflammatory cytokine storms associated with severe cases of COVID-19.

immunology↗
bioRxiv2020

Transferrin receptor is another receptor for SARS-CoV-2 entry

Angiotensin-converting enzyme 2 (ACE2) has been suggested as a receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry to cause coronavirus disease 2019 (COVID-19). However, no ACE2 inhibitors have shown definite beneficiaries for COVID-19 patients, applying the presence of another receptor for SARS-CoV-2 entry. Here we show that ACE2 knockout dose not completely block virus entry, while TfR directly interacts with virus Spike protein to mediate virus entry and SARS-CoV-2 can infect mice with over-expressed humanized transferrin receptor (TfR) and without humanized ACE2. TfR-virus co-localization is found both on the membranes and in the cytoplasma, suggesting SARS-CoV-2 transporting by TfR, the iron-transporting receptor shuttling between cell membranes and cytoplasma. Interfering TfR-Spike interaction blocks virus entry to exert significant anti-viral effects. Anti-TfR antibody (EC50 ~16.6 nM) shows promising anti-viral effects in mouse model. Collectively, this report indicates that TfR is another receptor for SARS-CoV-2 entry and a promising anti-COVID-19 target.

microbiology↗
bioRxiv2020

Enhanced ultrasound neuromodulation in vitro using nanobubble actuators

Ultrasound neuromodulation is a promising new method to manipulate brain activity noninvasively. Here, we detail a neurostimulation scheme using gas-filled nanostructures, gas vesicles (GVs), as actuators for improving the efficacy and precision of ultrasound stimuli. Sonicated primary neurons displayed dose-dependent, repeatable Ca2+ responses, closely synced to stimuli, and increased nuclear expression of the activation marker c-Fos only in the presence of GVs but not without. We identified mechanosensitive ion channels as important mediators of this effect, and neurons heterologously expressing the mechanosensitive MscL-G22S channel showed greater activation at lower acoustic pressure. This treatment scheme was also found not to induce significant cytotoxicity, apoptosis or membrane poration in treated cells. Altogether, we demonstrate a simple and effective method to achieve enhanced and more selective ultrasound neurostimulation. Graphical abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

neuroscience↗
bioRxiv2020

Genome sequencing sheds light on the contribution of structural variants to Brassica oleracea diversification

Brassica oleracea includes several morphologically diverse, economically important vegetable crops. Here we present high-quality chromosome-scale genome assemblies for two B. oleracea morphotypes, cauliflower and cabbage. Direct comparison of these two assemblies identifies ~120 K high-confidence structural variants (SVs). Population analysis of 271 B. oleracea accessions using these SVs clearly separates different morphotypes, suggesting the association of SVs with B. oleracea intraspecific divergence. Genes affected by SVs selected between cauliflower and cabbage are enriched with functions related to response to stress and stimulus and meristem and flower development. Furthermore, genes affected by selected SVs and involved in the switch from vegetative to generative growth that defines curd initiation, inflorescence meristem proliferation for curd formation, maintenance and enlargement, are identified, providing insights into the regulatory network of curd development. This study reveals the important roles of SVs in diversification of different morphotypes of B. oleracea, and the newly assembled genomes and the SVs provide rich resources for future research and breeding.

plant biology↗
bioRxiv2020

A COVID-19 antibody curbs SARS-CoV-2 nucleocapsid protein-induced complement hyper-activation

Although human antibodies elicited by severe acute respiratory distress syndrome coronavirus-2 (SARS-CoV-2) nucleocapsid (N) protein are profoundly boosted upon infection, little is known about the function of N-directed antibodies. Herein, we isolated and profiled a panel of 32 N protein-specific monoclonal antibodies (mAb) from a quick recovery coronavirus disease-19 (COVID-19) convalescent, who had dominant antibody responses to SARS-CoV-2 N protein rather than to Spike protein. The complex structure of N protein RNA binding domain with the highest binding affinity mAb nCoV396 reveals the epitopes and antigens allosteric changes. Functionally, a virus-free complement hyper-activation analysis demonstrates that nCoV396 specifically compromises N protein-induced complement hyper-activation, a risk factor for morbidity and mortality in COVID-19, thus paving the way for functional anti-N mAbs identification. One Sentence SummaryB cell profiling, structural determination, and protease activity assays identify a functional antibody to N protein.

molecular biology↗
bioRxiv2020

A non-canonical EZH2 function sensitizes solid tumors to genotoxic stress

Drugs that block the activity of the methyltransferase EZH2 are in clinical development for the treatment of non-Hodgkin lymphomas harboring gain-of-function EZH2 mutations that enhance its polycomb repressive function. In contrast, in castration-resistant prostate cancer (CRPC) we have previously reported that EZH2 plays a non-canonical role as a transcriptional activator. In this setting, we now show that EZH2 inhibitors can also block the non-canonical activity of EZH2 and inhibit the growth of CRPC cells. Gene expression and epigenomic profiling of cells treated with EZH2 inhibitors demonstrated that rather than de-repressing tumor suppressor genes silenced by PRC2, EZH2 inhibitors downregulate a set of DNA repair genes that are directly regulated by EZH2. In addition, genome-wide CRISPR/Cas9-mediated loss-of-function screens in the presence of EZH2 inhibitors identified these DNA repair genes to underlie the growth-inhibitory function of these compounds. Interrogation of public data from diverse solid tumor types expressing wild-type EZH2 showed that expression of DNA damage repair genes is significantly correlated with cellular sensitivity to EZH2 inhibitors. Consistent with these findings, treatment of CRPC cells with EZH2 inhibitors dramatically enhanced their sensitivity to genotoxic stress. These studies reveal a previously unappreciated mechanism of action of EZH2 inhibitors and provide a mechanistic basis for potential new combination cancer therapies.

cancer biology↗
bioRxiv2020

Control of ss-glucan exposure by the endo-1,3-glucanase Eng1 in Candida albicans modulates virulence

Candida albicans is a major cause of invasive candidiasis, which has a high mortality rate. The hyphal form of C. albicans is virulent and activates the host innate immune response, while the yeast form is hypovirulent and less immunogenic. The innate immune response is critical for host defense, but overactivation can cause tissue damage and sepsis. The innate immune response can be triggered when the C-type lectin receptor Dectin-1 recognizes {beta}-glucans, which is protected by the outer mannan layer of the cell wall on C. albicans. Here, we demonstrate that there is low level of Dectin-1 binding at the septum of yeast cells, but high level of Dectin-1 binding over the entire surface of hyphae. We find that {beta}-glucan masking in yeast is controlled by two highly expressed yeast proteins, the endo-1,3-{beta}-glucanase Eng1 and the Yeast Wall Protein Ywp1. An eng1 deletion mutant shows enhanced Dectin-1 binding at the septa, while an eng1 ywp1 double mutant, but not an ywp1 single mutant, shows strong overall Dectin-1 binding. Thus, Eng1-mediated {beta}-glucan trimming and Ywp1-mediated {beta}-glucan masking are two parallel mechanisms utilized by C. albicans yeast to minimize recognition by Dectin-1. In the model of disseminated candidiasis, mice infected with the eng1 deletion mutant showed delayed mortality with an increased renal immune response in males compared to mice infected with the wild-type strain, but earlier mortality with a higher renal immune response in females. Using the eng1 mutant that is specifically defective in {beta}-glucan masking in yeast, this study demonstrates that the level of {beta}-glucan exposure is important for modulating the balance between immune protection and immunopathogenesis. Abstract ImportanceCandida albicans is a major opportunistic fungal pathogen of humans. Systemic Candidiasis has high mortality rates. C. albicans is also a constituent of the human microbiome and found in gastrointestinal and genitourinary tracts of most healthy individuals. C. albicans is able to switch reversibly between yeast and hyphae in response to environmental cues. The hyphal form is virulent, while the yeast form is hypovirulent and less immunogenic. This study demonstrates that {beta}-glucan exposure in yeast is protected by two highly expressed yeast proteins, the endo-1,3-{beta}-glucanase Eng1 and the Yeast Wall Protein Ywp1. Eng1-mediated {beta}-glucan trimming and Ywp1-mediated {beta}-glucan masking are two parallel mechanisms utilized by C. albicans yeast to minimize recognition by the host C-type lectin receptor Dectin-1. The eng1 mutant triggers a higher immune response and leads to earlier mortality compared to the wild-type strain. Thus, {beta}-glucan masking in yeast keeps yeast cells less immunogenic and hypovirulent.

microbiology↗
bioRxiv2020

In-depth analysis reveals complex molecular etiology of idiopathic cerebral palsy

Cerebral palsy (CP), the most prevalent physical disability in children, has long been ignored with regard to its inherent molecular mechanism. In this work, we performed in-depth clinical and molecular analysis on 120 idiopathic CP families, and identified in half of the patients the underlying risk factors. By a compilation of 117 CP-related genes, we recognized the characteristic features in terms of inheritance and function, and proposed a dichotomous classification system according to the expression patterns. In two patients with both CP and intellectual disability, we revealed that the defective TYW1, a tRNA hypermodification enzyme, caused microcephaly and problems in motion and cognition by hindering neuronal proliferation and migration. We developed an algorithm and proved in mice brain that this malfunctioning hypermodification specifically perturbed the translation of a subset of proteins involved in cell cycling. In a CP patient with normal intelligence, we identified a mitochondrial enzyme GPAM, the hypomorphic form of which led to hypomyelination of corticospinal tract. We confirmed that the aberrant Gpam in mice perturbed the lipid metabolism in astrocyte, resulting in suppressed astrocyte proliferation and a shortage of lipid contents supplied for oligodendrocyte myelination. This work broadened the scope of understanding of CP etiology and paved a way for innovative therapeutic strategies.

genetics↗
bioRxiv2020

MicroPhenoDB associates metagenomic data with pathogenic microbes, microbial core genes, and human disease phenotypes

Microbes play important roles in human health and disease. The interaction between microbes and hosts is a reciprocal relationship, which remains largely under-explored. Current computational resources lack manually and consistently curated data to connect metagenomic data to pathogenic microbes, microbial core genes, and disease phenotypes. We developed the MicroPhenoDB database by manually curating and consistently integrating microbe-disease association data. MicroPhenoDB provides 5677 non-redundant associations between 1781 microbes and 542 human disease phenotypes across more than 22 human body sites. MicroPhenoDB also provides 696,934 relationships between 27,277 unique clade-specific core genes and 685 microbes. Disease phenotypes are classified and described using the Experimental Factor Ontology (EFO). A refined score model was developed to prioritize the associations based on evidential metrics. The sequence search option in MicroPhenoDB enables rapid identification of existing pathogenic microbes in samples without running the usual metagenomic data processing and assembly. MicroPhenoDB offers data browsing, searching and visualization through user-friendly web interfaces and web service application programming interfaces. MicroPhenoDB is the first database platform to detail the relationships between pathogenic microbes, core genes, and disease phenotypes. It will accelerate metagenomic data analysis and assist studies in decoding microbes related to human diseases. MicroPhenoDB is available through http://www.liwzlab.cn/microphenodb and http://lilab2.sysu.edu.cn/microphenodb.

bioinformatics↗
bioRxiv2020

A novel bioinformatics approach to reveal the role of circadian oscillations in AD development

Altered circadian gene expression may contribute to Alzheimers disease (AD) progression. Unfortunately, sampling the central nervous system (CNS) at multiple time points is not feasible. Moreover, there are no AD-related time-series transcriptome datasets available for studying these circadian patterns and their impacts on AD development. In this study, we introduce a novel computational platform, Event-driven Sample Ordering for Circadian Variation Detection (ESOCVD), to reveal rhythmic patterns of gene expression of AD using untimed transcriptome datasets. ESOCVD was applied to 20 untimed gene expression profiles of 16 brain regions from approximately 3000 AD patients in public transcriptome databases. Our analysis revealed five types of circadian alteration patterns in ~2,000 circadian genes in different brain regions of AD patients. Further analyses of additional databases confirmed that our analytical platform can be applied to identify the evolutionary dynamics of circadian variation during the process of AD development. Through the gene expression correlation analysis for our 8 circadian genes identified from AMP-AD MSBB cohorts, we identified stage-specifically enriched biological processes with anticipated context. Gene expression analysis of AD mouse brain tissues further substantiated the predictions of the ESOCVD model. In summary, ESOCVD is highly versatile in bridging circadian research and precision medicine.

bioinformatics↗
bioRxiv2020

NF45/NF90-mediated rDNA transcription provides a novel target for immunosuppressant development

Herein, we demonstrate that NFAT, a key regulator of the immune response, translocates from cytoplasm to nucleolus and interacts with NF45/NF90 complex to collaboratively promote rDNA transcription via triggering the directly binding of NF45/NF90 to the ARRE2-like sequences in rDNA promoter upon T cell activation in vitro. The elevated pre-rRNA level of T cells is also observed in both mouse heart or skin transplantation models, and in kidney transplanted patients. Importantly, T cell activation can be significantly suppressed by inhibiting NF45/NF90-dependent rDNA transcription. Amazingly, CX5461, a rDNA transcription specific inhibitor, outperformed FK506, the most commonly used immunosuppressant, both in terms of potency and off-target activity (i.e. toxicity), as demonstrated by a series of skin and heart allograft models. Collectively, this reveals NF45/NF90-mediated rDNA transcription as a novel signaling pathway essential for T cell activation and as a new target for the development of safe and effective immunosuppressants.

molecular biology↗
bioRxiv2020

Genomic analysis of worldwide sheep breeds reveals PDGFD a major target of fat-tail selection in sheep

Fat tail is a special trait in sheep acquired during sheep domestication. Several genomic analyses have been conducted in sheep breeds from limited geographic origins to identify the genetic factors underlying this trait. Nevertheless, these studies obtained different candidates. The results of these regional studies were easily biased by the breed structures. To minimize the bias and distinguish the true candidates, we used an extended data set of 968 sheep representing 18 fat-tailed breeds and 14 thin-tailed breeds from around the world, and integrated two statistic tests to detect selection signatures, including Genetic Fixation Index (FST) and difference of derived allele frequency ({Delta}DAF). The results showed that platelet derived growth factor D (PDGFD) exhibited the highest genetic differentiation between fat- and thin-tailed sheep breeds. Further analysis of sequence variation identified that a 6.8-kb region within the first intron of PDGFD is likely the target of positive selection and contains regulatory mutation(s) in fat-tailed sheep. Histological analysis and gene expression analysis demonstrated that PDGFD expression is associated with maturation and hemostasis of adipocytes. Luciferase reporter assays showed that a segment of conserved sequence surrounding the orthologous site of one sheep mutation is functional in regulating PDGFD expression in human. These results reveal that PDGFD is the predominant factor for the fat tail phenotype in sheep by contributing to adiopogenesis and maintaining the hemostasis of mature adipocytes. This study provides insights into the evolution of fat-tailed sheep and has important application to animal breeding, as well as obesity-related human diseases.

genomics↗
bioRxiv2020

Neurodevelopmental deficits and cell-type-specific transcriptomic perturbations in a mouse model of HNRNPU haploinsufficiency

Heterozygous de novo loss-of-function mutations in the gene expression regulator HNRNPU cause an early-onset developmental and epileptic encephalopathy. To gain insight into pathological mechanisms and lay the potential groundwork for developing targeted therapies, we characterized the neurophysiologic and cell-type-specific transcriptomic consequences of a mouse model of HNRNPU haploinsufficiency. Heterozygous mutants demonstrated neuroanatomical abnormalities, global developmental delay, impaired ultrasonic vocalizations and increased seizure susceptibility, thus modeling aspects of the human disease. Single-cell RNA-sequencing of hippocampal and neocortical cells revealed widespread, yet modest, dysregulation of gene expression across mutant neuronal subtypes. We observed an increased burden of differentially-expressed genes in mutant excitatory neurons of the subiculum--a region of the hippocampus implicated in temporal lobe epilepsy. Evaluation of transcriptomic signature reversal as a therapeutic strategy highlights the potential importance of generating cell-type-specific signatures. Overall, this work provides insight into HNRNPU-mediated disease mechanisms, and provides a framework for using single-cell RNA-sequencing to study transcriptional regulators implicated in disease.

neuroscience↗
bioRxiv2020

Susceptibility of tree shrew to SARS-CoV-2 infection

Since SARS-CoV-2 became a pandemic event in the world, it has not only caused huge economic losses, but also a serious threat to global public health. Many scientific questions about SARS-CoV-2 and COVID-19 were raised and urgently need to be answered, including the susceptibility of animals to SARS-CoV-2 infection. Here we tested whether tree shrew, an emerging experimental animal domesticated from wild animal, is susceptible to SARS-CoV-2 infection. No clinical signs were observed in SARS-CoV-2 inoculated tree shrews during this experiment except the increasing body temperature (above 39{degrees} C) particular in female animals during infection. Low levels of virus shedding and replication in tissues occurred in all three age groups, each of which showed his own characteristics. Histopathological examine revealed that pulmonary abnormalities were mild but the main changes although slight lesions were also observed in other tissues. In summary, tree shrew is not susceptible to SARS-CoV-2 infection and may not be a suitable animal for COVID-19 related researches.

microbiology↗