Biology subjects

Gong, Y.

Publications and source records attributed to Gong, Y..

At least 109 records · Page 6Linked to original sources

bioRxiv2021

On the edge: Evolution of polarity protein BASL and the capacity for stomatal lineage asymmetric divisions

Asymmetric and oriented stem cell divisions enable the continued production of patterned tissues. The molecules that guide these divisions include several "polarity proteins" that are localized to discrete plasma membrane domains, are differentially inherited during asymmetric divisions, and whose scaffolding activities can guide division plane orientation and subsequent cell fates. In the stomatal lineages on the surfaces of plant leaves, asymmetric and oriented divisions create distinct cell types in physiologically optimized patterns. The polarity protein BASL is a major regulator of stomatal lineage division and cell fate asymmetries in Arabidopsis, but its role in the stomatal lineages of other plants is unclear. Here, using phylogenetic and functional assays, we demonstrate that BASL is a eudicot-specific polarity protein. Among dicots, divergence in BASLs roles may reflect some intrinsic protein differences, but more likely reflects previously unappreciated differences in how asymmetric cell divisions are employed for pattern formation in different species. This multi-species analysis therefore provides insight into the evolution of a unique polarity regulator and into the developmental choices available to cells as they build and pattern tissues. HIGHLIGHTSO_LIBASL is a eudicot-specific regulator of stomatal lineage asymmetric cell divisions C_LIO_LIBASL protein evolution includes stepwise addition of polarity domains to an ancestral MAPK-binding chassis C_LIO_LICellular quiescence and BASL-guided polarity generate proper stomatal spacing in tomato C_LIO_LICell size and fate asymmetries are uncoupled in the tomato stomatal lineage C_LI

plant biology↗

bioRxiv2021

Arabidopsis stomatal polarity protein BASL mediates distinct processes before and after cell division to coordinate cell size and fate asymmetries

In many land plants, asymmetric cell divisions (ACDs) create and pattern differentiated cell types on the leaf surface. In the Arabidopsis stomatal lineage, BREAKING OF ASYMMETRY IN THE STOMATAL LINEAGE (BASL) regulates multiple aspects of ACD including division plane placement and cell fate enforcement. Polarized subcellular localization of BASL is initiated before the ACD and persists for many hours after the division in one of the two daughters. Untangling the respective contributions of polarized BASL before and after division is essential to gain a better understanding of its roles in regulating stomatal lineage ACDs and to uncover the rules that guide leaf pattern. Here we combine quantitative imaging and lineage tracking with genetic tools that provide temporally-restricted BASL expression. We find that pre-division BASL is required for division orientation, whereas BASL polarity post-division ensures proper cell fate commitment. These genetic manipulations allowed us to uncouple daughter-cell size asymmetry from polarity crescent inheritance, revealing independent effects of these two asymmetries on subsequent cell behavior. Finally, we show that there is coordination between the division frequencies of sister cells produced by ACDs, and this coupling requires BASL as an effector of peptide signaling.

plant biology↗

bioRxiv2021

miR-2 contributes to WSSV infection by targeting Caspase 2 in mud crab (Scylla paramamosain)

As we known, Caspase 2 is widely studied for its apoptosis regulatory function in mammals. However, despite the fundamental role of apoptosis during the anti-viral immune response, the relationship between Caspase 2 and virus infection has not been extensively explored in invertebrates, whether miRNAs are involved in this process also remains unclear. To address this issue, the miRNA-mediated regulation of Caspase 2 in mud crab Scylla paramamosain was characterized in this study. The results suggested that Sp-Caspase 2 could suppress white spot syndrome virus (WSSV) infection via apoptosis induction. The further data showed that Caspase 2 was directly targeted by miR-2 in mud crab. Silencing or overexpression of miR-2 could affect apoptosis and WSSV replication through regulating the expression level of Caspase 2. Taken together, all these results demonstrated the crucial role of miR-2-Caspase 2 pathway in the innate immunity of mud crab and revealed a novel mechanism during anti-viral immune response in marine invertebrates.

immunology↗

bioRxiv2021

TCR signaling promotes the assembly of RanBP2/RanGAP1-SUMO1/Ubc9 NPC subcomplex via phosphorylation of RanGAP1 by PKC-θ

The nuclear pore complex (NPC) is the sole and selective gateway for nuclear transport and its dysfunction has been associated with many diseases. The NPC subcomplex RanBP2, which consists of RanBP2 (Nup358), RanGAP1-SUMO1 and Ubc9, regulates the assembly and function of the NPC. The roles of immune signaling in NPC assembly remain poorly understood. Here, we show that, following TCR stimulation, protein kinase C-{theta} (PKC-{theta}) directly phosphorylates RanGAP1 to facilitate RanBP2 subcomplex assembly and nuclear import and, thus, the nuclear translocation of AP-1 transcription factor. Mechanistically, TCR stimulation induces the translocation of activated PKC-{theta} to the NPC, where it interacts with and phosphorylates RanGAP1 on Ser504 and Ser506. RanGAP1 phosphorylation increases its binding affinity for Ubc9, thereby promoting sumoylation of RanGAP1 and, finally, assembly of the RanBP2 subcomplex. Our findings reveal an unexpected role of PKC-{theta} as a direct regulator of nuclear import and uncover a phosphorylation-dependent sumoylation of RanGAP1, delineating a novel link between TCR signaling and assembly of the RanBP2 NPC subcomplex.

cell biology↗

bioRxiv2021

Young and Undamaged rMSA Improves the Longevity of Mice

Improvement of longevity is an eternal dream of human beings. Here we report that a single protein recombinant mouse serum albumin (rMSA) improved the lifespan and healthspan of C57BL/6N mice. The median lifespan extensions were 17.6% for female and 20.3% for male, respectively. The grip strength of rMSA-treated female and male mice increased by 29.6% and 17.4%, respectively. Meanwhile, the percentage of successful escape increased 23.0% in rMSA-treated male mice using the Barnes Maze test. The rMSA used in this study is young and almost undamaged. We define the concept "young and undamaged" to any protein without any unnecessary modifications by four parameters: intact free thiol (if any), no advanced glycation end-product, no carbonylation, and no homocysteinylation. Here "young and undamaged" rMSA is much younger and less damaged than the endogenous serum albumin from young mice at 1.5 months of age. We predict that young and undamaged proteins altogether can further improve the longevity.

biochemistry↗

bioRxiv2021

A novel Wnt/beta-catenin signaling driven adipocyte population that is required for beiging

Wnt/{beta}-catenin signaling has been well established as a potent inhibitor of adipogenesis. Here, we identified a population of adipocytes that exhibit persistent activity of Wnt/{beta}-catenin signaling, as revealed by the Tcf/Lef-Gfp reporter allele, in embryonic and adult mouse fat depots, named as Wnt+ adipocytes. We showed that the {beta}-catenin-mediated signaling activation in these cells is Wnt ligand- and receptor-independent but relies on AKT/mTOR pathway and is essential for cell survival. Such adipocytes are distinct from classical ones in transcriptomic and genomic signatures and can be induced from various sources of mesenchymal stromal cells including human cells. Genetic lineage-tracing and targeted cell ablation studies revealed that these adipocytes convert into beige adipocytes directly and are also required for beige fat recruitment under thermal challenge, demonstrating both cell autonomous and non-cell autonomous roles in adaptive thermogenesis. Furthermore, mice bearing targeted ablation of these adipocytes exhibited glucose intolerance, while mice receiving exogenously supplied such cells manifested enhanced glucose utilization. Our studies uncover a unique adipocyte population in regulating beiging in adipose tissues and systemic glucose homeostasis.

physiology↗

bioRxiv2020

Landscapes and dynamic diversifications of B-cell receptor repertoires in COVID-19 patients

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the pandemic of coronavirus disease 2019 (COVID-19). Great international efforts have been put into the development of prophylactic vaccines and neutralizing antibodies. However, the knowledge about the B cell immune response induced by the SARS-CoV-2 virus is still limited. Here, we report a comprehensive characterization of the dynamics of immunoglobin heavy chain (IGH) repertoire in COVID-19 patients. By using next-generation sequencing technology, we examined the temporal changes in the landscape of the patients immunological status, and found dramatic changes in the IGH within the patients immune system after the onset of COVID-19 symptoms. Although different patients have distinct immune responses to SARS-CoV-2 infection, by employing clonotype overlap, lineage expansion and clonotype network analyses, we observed a higher clonotype overlap and substantial lineage expansion of B cell clones during 2-3 weeks of illness, which is of great importance to B-cell immune responses. Meanwhile, for preferences of V gene usage during SARS-CoV-2 infection, IGHV3-74 and IGHV4-34 and IGHV4-39 in COVID-19 patients were more abundant than that of healthy controls. Overall, we present an immunological resource for SARS-CoV-2 that could promote both therapeutic development as well as mechanistic research.

immunology↗

bioRxiv2020

An Ultrasensitive Biosensor for Quantifying the Interaction of SARS-CoV-2 and Its Receptor ACE2 in Cells and in vitro

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is currently spreading and mutating with increasing speed worldwide. Therefore, there is an urgent need for a simple, sensitive, and high-throughput (HTP) assay to quantify virus-host interaction in order to quickly evaluate infectious ability of mutant virus and develop or validate virus-inhibiting drugs. Here we have developed an ultrasensitive bioluminescent biosensor to evaluate virus-cell interaction by quantifying the interaction between SARS-CoV-2 receptor binding domain (RBD) and its cellular receptor angiotensin-converting enzyme 2 (ACE2) both in living cells and in vitro. We have successfully used this novel biosensor to analyze SARS-CoV-2 RBD mutants, and evaluated candidate small molecules (SMs), antibodies, and peptides that may block RBD:ACE2 interaction. This simple, rapid and HTP biosensor tool will significantly expedite detection of viral mutants and anti-COVID-19 drug discovery processes.

biochemistry↗

bioRxiv2020

X-MOL: large-scale pre-training for molecular understanding and diverse molecular analysis

In silico modelling and analysis of small molecules substantially accelerates the process of drug development. Representing and understanding molecules is the fundamental step for various in silico molecular analysis tasks. Traditionally, these molecular analysis tasks have been investigated individually and separately. In this study, we presented X-MOL, which applies large-scale pre-training technology on 1.1 billion molecules for molecular understanding and representation, and then, carefully designed fine-tuning was performed to accommodate diverse downstream molecular analysis tasks, including molecular property prediction, chemical reaction analysis, drug-drug interaction prediction, de novo generation of molecules and molecule optimization. As a result, X-MOL was proven to achieve state-of-the-art results on all these molecular analysis tasks with good model interpretation ability. Collectively, taking advantage of super large-scale pre-training data and super-computing power, our study practically demonstrated the utility of the idea of "mass makes miracles" in molecular representation learning and downstream in silico molecular analysis, indicating the great potential of using large-scale unlabelled data with carefully designed pre-training and fine-tuning strategies to unify existing molecular analysis tasks and substantially enhance the performance of each task.

bioinformatics↗

bioRxiv2020

Dissecting human skeletal stem cell ontogeny by single-cell transcriptomic and functional analyses

Human skeletal stem cells (SSCs) have been discovered in fetal and adult bones. However, the spatiotemporal ontogeny of human SSCs during embryogenesis has been elusive. Here we map the transcriptional landscape of human embryonic skeletogenesis at single-cell resolution to address this fundamental question. We found remarkable heterogeneity within human limb bud mesenchyme and epithelium, as well as the earliest osteo-chondrogenic progenitors. Importantly, embryonic SSCs (eSSCs) were found in the perichondrium of human long bones, which self-renew and generate osteochondral lineage cells, but not adipocytes or hematopoietic stroma. eSSCs are marked by the adhesion molecule CADM1 and highly enrich FOXP1/2 transcriptional network. Interestingly, neural crest-derived cells with similar phenotypic markers and transcriptional network were also found in the sagittal suture of human embryonic calvaria. Taken together, this study revealed the cellular heterogeneity and lineage hierarchy during human embryonic skeletogenesis, and identified distinct skeletal stem/progenitor cells that orchestrate endochondral and intramembranous ossification.

developmental biology↗

bioRxiv2020

Exosomal miR-224 contributes to hemolymph microbiota homeostasis during bacterial infection in crustacean

The modulation of hemolymph microbiota homeostasis is vital for the marine invertebrate innate immunity, while growing evidence shows that exosomes could serves as anti-bacterial immune factors, however, the relationship between exosomes and hemolymph microbiota homeostasis during pathogenic bacteria infection has not been addressed. Here, we determined that exosomes released from Vibrio parahaemolyticus-infected Scylla paramamosain (mud crabs) could reduce the mortality of the host during the infection by maintaining the homeostasis of hemolymph microbiota. We further confirmed that miR-224 was densely packaged in these exosomes and targeting to HSP70, which resulted in disruption of the HSP70-TRAF6 complex to release TRAF6 that allows it to interact with Ecsit. The interaction of TRAF6 with Ecsit regulates the production of mitochondrial ROS (mROS) and Anti-lipopolysaccharide factors (ALFs) expression in recipient hemocytes, which affects homeostasis of hemolymph microbiota in response to the pathogenic bacteria infection in mud crab. To the best of our knowledge, this is the first document that reports the role of exosome in the homeostasis of hemolymph microbiota during pathogen infection and a novel regulatory mechanism and crosstalk between exosomal miRNAs and innate immune response in crustaceans. Author summaryExosomes are small membrane vesicles of endocytic origin which are widely involved in the regulation of a variety of pathological processes in mammals. Yet, although the antibacterial function of exosomes has been discovered for many years, the relationship between exosomes and hemolymph microbiota homeostasis remains unknown. In the present study, we identified the miRNAs packaged by exosomes that were possibly involved in Vibrio parahaemolyticus infection by modulating hemolymph microbiota homeostasis in crustacean mud crab Scylla paramamosain. Moreover, it was found that miR-224 was densely packaged in exosomes after Vibrio parahaemolyticus challenge, resulting in the suppression of HSP70 and disruption of the HSP70-TRAF6 complex in recipient hemocytes, then the released TRAF6 was further interacted with Ecsit to regulate ROS and ALFs levels, which eventually affected hemolymph microbiota homeostasis to cope with pathogenic bacteria infection. Our finding is the first to reveal the relationship between exosomes and hemolymph microbiota homeostasis in animals, which shows a novel molecular mechanism of invertebrate resistance to pathogenic microbial infection.

immunology↗

bioRxiv2020

Target lipidomics reveals associations between serum sphingolipids and insulin sensitivity by the glucose clamp

BackgroundThis study aimed to systematically investigate the associations between serum sphingolipids and insulin sensitivity as well as insulin secretion. This study also aimed to reveal potential predictors for insulin sensitivity or give perceptive insight into disease processes. MethodsWe conducted a lipidomics evaluation of molecularly distinct SPs in the serum of 86 consecutive Chinese adults with or without obesity and diabetes using electrospray ionization mass spectrometry coupled with liquid chromatography. The GIR30 was measured under steady conditions to assess insulin sensitivity by the gold standard hyperinsulinemic-euglycemic clamp. We created the ROC curves to detect the serum SMs diagnostic value and establish the diagnosis of insulin sensitivity. ResultsDifferential correlation network analysis illustrated correlations amongst lipids, insulin sensitivity, insulin secretion and other clinical indexes. Total and subspecies of serum SMs and globotriaosylceramides (Gb3s) were positively related to GIR30, free FAs (FFA 16:1, FFA20:4), some long chain GM3 and complex ceramide GluCers showed strong negative correlations with GIR30. Notably, ROC curves showed that SM/Cer and SM d18:0/26:0 may be good serum lipid predictors of diagnostic indicators of insulin sensitivity close to conventional clinical indexes such as 1/HOMA-IR (all areas under the curve >0.80) based on GIR30 as standard diagnostic criteria. ConclusionsThese results provide novel associations between serum sphingolipid between insulin sensitivity measured by the hyperinsulinemic-euglycemic clamp. We further identify two specific SPs that may represent prognostic biomarkers for insulin sensitivity.

physiology↗

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

Genome engineering of Nannochloropsis with large deletions for constructing microalgal minigenomes

Industrial microalgae are promising photosynthetic cell factories, yet tools for targeted genome engineering are limited. Here for the model industrial oleaginous microalga Nannochloropsis oceanica we established a method to precisely and serially delete large genome fragments of ~100 kb from its 30.01-Mb nuclear genome. We started by identifying the "non-essential" chromosomal regions (i.e., low-expression region or LER) based on minimal gene expression under N-replete and N-depleted conditions. The largest such LER (LER1) is ~98 kb in size, located near the telomere of the 502.09 kb-long Chromosome 30 (Chr 30). We deleted 81 kb and further distal and proximal deletions of up to 110 kb (21.9% of Chr 30) in LER1 by dual targeting the boundaries with the episome-based CRISPR/Cas9 system. The telomere-deletion mutants showed normal telomeres consisting of CCCTAA repeats, revealing telomere regeneration capability after losing distal part of Chr 30. Interestingly, the deletions caused no significant alteration in growth, lipid production or photosynthesis (transcript-abundance change for < 3% genes under N depletion). We also performed double-deletion of both LER1 and LER2 (from Chr 9) that totals ~214 kb, and phenotypes are essentially normal. Therefore, loss of the large yet "non-essential" regions does not necessarily sacrifice important traits. Such serial targeted deletions of large genomic regions have not been reported in plants or microalgae, and will accelerate crafting minimal genomes as chassis for photosynthetic production.

biochemistry↗

bioRxiv2020

NDRG1 expression is an independent prognostic factor in inflammatory breast cancer

NDRG1 is widely described as a metastasis suppressor in breast cancer. However, we found that NDRG1 is critical in promoting tumorigenesis and brain metastasis in mouse models of inflammatory breast cancer (IBC), a rare but highly aggressive form of breast cancer. We hypothesized that NDRG1 is a prognostic marker associated with poor outcome in patients with IBC. Microarray gene expression data from the IBC Consortium dataset were analyzed to compare NDRG1 expression between IBC and non-IBC tumors and among breast cancer subtypes. NDRG1 levels in tissue microarrays from 64 IBC patients were evaluated by immunohistochemical staining with anti-NDRG1 primary antibody (32 NDRG1-low [[≤] median], 32 NDRG1-high [>median]). Overall and disease-free survival (OS and DSS) were analyzed with Kaplan-Meier curves and log-rank test. NDRG1 mRNA expression was higher in IBC than in non-IBC tumors (p=0.007), and in more aggressive HER2+ and basal-like vs luminal IBC subtypes (p<0.0001). Univariate analysis showed NDRG1 expression, tumor grade, disease stage, estrogen receptor (ER) status, and receipt of adjuvant radiation to be associated with OS and DSS. NDRG1-high patients had poorer 10-year OS and DSS than NDRG1-low patients (OS, 19% vs 45%, p=0.0278; DSS, 22% vs 52%, p=0.0139). On multivariable analysis, NDRG1 independently predicted OS (hazard ratio [HR]=2.034, p=0.0274) and DSS (HR=2.287, p=0.0174). NDRG1-high ER-negative tumors had worse outcomes OS, p=0.0003; DSS, p=0.0003; and NDRG1-high tumors that received adjuvant radiation treatment had poor outcomes (OS, p=0.0088; DSS, p=0.0093). NDRG1 correlated positively with aggressive tumor characteristics in IBC and was a significant independent prognostic factor for DSS and OSS in IBC patients. Targeting NDRG1 may represent a novel strategy for improving clinical outcomes for patients with IBC.

cancer biology↗

bioRxiv2020

WSB1 Regulates c-Myc Expression Through β-catenin Signaling and Forms a Feedforward Circuit Promoting the Development of Cancer.

The dysregulation of transcription factors is widely associated with tumorigenesis. As the most well-defined transcription factor in multiple types of cancer, c-Myc can directly transform cells by transactivating various downstream genes. Given that there is no effective way to directly inhibit c-Myc, c-Myc targeting strategies based on its regulatory mechanism hold great potential for cancer therapy. In this study, we found that WSB1, a direct target gene of c-Myc, can positively regulate c-Myc expression, which forms a feedforward circuit promoting cancer development. Luciferase-based promoter activity assays and RNA sequencing results confirmed that WSB1 promoted c-Myc expression through the {beta}-catenin pathway. Mechanistically, WSB1 affected {beta}-catenin destruction complex-PPP2CA assembly and E3 ubiquitin ligase adaptor {beta}-TRCP recruitment, which inhibited the ubiquitination of {beta}-catenin and subsequently transactivated c-Myc. Of interest, the promoting effect of WSB1 on c-Myc was independent of its E3 ligase activity. Moreover, co-expression of WSB1 and c-Myc strongly enhanced the initiation and progression of tumours both in vitro and in vivo. Thus, our findings revealed a novel mechanism involved in tumorigenesis in which the WSB1/c-Myc feedforward circuit played an essential role, highlighting a potential c-Myc intervention strategy in cancer treatment.

molecular biology↗

bioRxiv2020

Tuning of self-renewing capacity in theArabidopsis stomatal lineage by hormonaland nutrition regulation of asymmetric celldivisions

Asymmetric and self-renewing divisions build and pattern tissues. In the Arabidopsis thaliana stomatal lineage, asymmetric cell divisions, guided by polarly localized cortical proteins, generate the majority of cells on the leaf surface. These divisions can be fine-tuned by systemic and environmental signals to modify tissue development, but the molecular mechanisms by which plants incorporate such cues to regulate asymmetric divisions are largely unknown. In a screen for modulators of cell polarity and asymmetric divisions, we identified a mutation in CONSTITIUTIVE TRIPLE RESPONSE 1, a negative regulator of ethylene signaling. We subsequently revealed antagonistic impacts of ethylene and glucose signaling on the self-renewing capacity of stomatal lineage stem cells. Quantitative analysis of the impacts of these signaling systems on cell polarity and fate dynamics showed that developmental information may be encoded in both the spatial and temporal asymmetries of polarity proteins. Taken together, our results provide a framework for a mechanistic understanding of how systemic information such as nutritional status and environmental factors tune stem cell behavior in the stomatal lineage, ultimately enabling optimization of leaf size and cell-type composition.

plant biology↗

bioRxiv2020

Quantitative and dynamic cell polarity tracking in plant cells

Quantitative information on the spatiotemporal distribution of polarized proteins is central for understanding cell-fate determination, yet collecting sufficient data for statistical analysis is difficult to accomplish with manual measurements. Here we present POME, a semi-automated pipeline for the quantification of cell polarity, and demonstrate its application to a variety of developmental contexts. POME analysis reveals that during asymmetric cell divisions in the Arabidopsis thaliana stomatal lineage, polarity proteins BASL and BRXL2 are more asynchronous and less mutually dependent than previously thought. While their interaction is important to maintain their polar localization and recruit other effectors to regulate asymmetric cell divisions, BRXL2 polarization precedes that of BASL and can be initiated in BASLs absence. Uncoupling of polarization from BASL activity is also seen in Brachypodium distachyon, where we find that the MAPKKK BdYDA1 is segregated and polarized following asymmetric division. Our results demonstrate that POME is a versatile tool, which by itself or combined with tissue-level studies and advanced microscopy techniques can help uncover new mechanisms of cell polarity.

cell biology↗