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Sun, M.

Publications and source records attributed to Sun, M..

At least 127 records · Page 7Linked to original sources
bioRxiv2022

Differential expression patterns and potential regulatory function of piRNAs in western honey bee larval response to Ascosphaera apis infestation

piRNAs are a class of small non-coding RNAs that play an essential part in genomic defense, as well as in modulation of gene expression and diverse biological processes such as host-pathogen interaction. However, little is known about the expression pattern of the regulatory function of piRNAs in interactions between honey bees and pathogens. In this work, on the basis of our previously obtained high-quality small RNA-seq datasets from western honey bee (Apis mellifera) larval guts, the differential expression profile of piRNAs in A. mellifera larval guts after Ascosphaera apis infestation was analyzed, followed by structural characterization, target prediction, and regulatory network investigation. The potential roles of differentially expressed piRNAs (DEpiRNAs) in regulating host response, especially immune response, were further discussed. In this study, 504, 657, and 587 piRNAs were respectively identified in the 4-, 5-, and 6-day-old larval guts infected by A. apis, with 411 (53.24%) piRNAs shared. The length distribution of these piRNAs ranged from 24 nt to 33 nt and their first base had a "C" bias, similar to piRNAs discovered in other mammals and insects. Additionally, 96, 103, and 143 DEpiRNAs were detected in the 4-, 5-, and 6-day-old comparison groups; among these, piR-ame-149736, piR-ame-1066173, and piR-ame-1125190 were the most up-regulated, while piR-ame-1202932 was the most down-regulated. There were 68 DEpiRNAs shared between these three comparison groups. The targets of the DEpiRNAs in the three comparison groups were engaged in a suite of crucial functions associated with biological processes, molecular function, and cellular components, including molecular transducer activity, biological regulation, and membrane part. These targets were also relevant to diverse vital pathways such as the phosphatidylinositol signaling system, inositol phosphate metabolism, and Wnt signaling pathway. Further investigation demonstrated that targets of DEpiRNAs were involved in three energy metabolism-related pathways, seven development-associated signaling pathways, and seven immune-relevant pathways, including lysosome and endocytosis, as well as the MAPK and Jak-STAT signaling pathways. The expression trends of five randomly selected DEpiRNAs were verified using a combination of RT-PCR and RT-qPCR. Moreover, the expression levels of six genes targeted by piR-ame-945760 were detected by RT-qPCR, with the results showing that their expression trends were the same as the expression trend of piR-ame-945760, indicative of the positive correlation between piR-ame-945760 and these targets. These results suggest that A.apis infestation increased the overall expression level of piRNAs and altered the expression pattern of piRNAs in A. mellifera larval guts. DEpiRNAs potentially participate in the A. apis response of the host by modulating the expression of target genes associated with energy metabolism and development, as well as cellular and humoral immune response. Our findings not only offer novel insights into A. mellifera larva-A. apis interaction, but also lay the groundwork for clarifying the mechanisms underlying DEpiRNA-regulated larval response.

molecular biology↗
bioRxiv2022

Arabidopsis ORP2A positively regulates glucose signaling by interacting with AtRGS1 and promoting AtRGS1 degradation

Heterotrimeric GTP-binding proteins (G proteins) are a group of regulators essential for signal transmission into cells. AtRGS1 (Regulator of G protein Signaling 1) with intrinsic GTPase-accelerating protein (GAP) activity could suppress G protein and glucose signal transduction in Arabidopsis. However, how AtRGS1 activity is regulated is currently poor understood. Here we identified a knockout mutant orp2a-1 (oxysterol-binding protein (OSBP)-related protein 2A) which shows phenotypes similar to agb1-2 (arabidopsis g-protein beta 1). With overexpression of ORP2A, transgenic lines display short hypocotyl, hypersensitivity to sugar and lower intracellular AtRGS1 level than control. Consistently, ORP2A shows interaction with AtRGS1 in vitro and vivo. Tissue specificity of ORP2A with two alternative protein forms imply its functions in organ size and shape controlling. Bioinformatic data and phenotypes of orp2a-1, agb1-2 and double mutant reveal genetic interactions in the regulation of G protein signaling and sugar response between ORP2A and G{beta}. Both alternative splicing forms of ORP2A locate in the ER, PM (Plasma Membrane) and EPCS (ER-PM Contact Sites), and interact with VAP27-1 mediated by a FFAT-like motif in vivo and vitro. ORP2A also displays differential phosphatidyl phosphoinositide binding activity mediated by its PH domain in vitro. Taken together, it is suggested that Arabidopsis membrane protein ORP2A interacts with AtRGS1 and VAP27-1 to positively regulate G protein and sugar signaling by facilitating AtRGS1 degradation.

plant biology↗
bioRxiv2022

First identification and investigation of piRNAs in the larval guts of Asian honey bee, Apis cerana

Piwi-interacting RNAs (piRNAs), a kind of small non-coding RNAs (ncRNAs), play pivotal parts in maintaining the genomic stability and modulating biological processes such as growth and development via regulation of gene expression. However, piRNAs in Asian honey bee (Apis cerana) is still largely unknown at present. In this current work, on basis of previously gained high-quality small RNA-seq datasets, piRNAs in the larval guts of Apis cerana cerana, the nominate species of A. cerana, was for the first time identified, followed by in-depth investigation of the regulatory roles of differentially expressed piRNAs (DEpiRNAs) in the developmental process of the A. c. cerana. Here, a total of 621 piRNAs were identified in the A. c. cerana larval guts, among which 499 piRNAs were shared by 4- (Ac4 group), 5- (Ac5 group), and 6-day-old (Ac6 group) larval guts, while the numbers of unique ones were 79, 37, and 11, respectively. piRNAs each group were ranged from 24 nt to 33 nt in length, and the first base of piRNAs had a cytosine (C) bias. Additionally, five up-regulated and five down-regulated piRNAs were identified in the Ac4 vs. Ac5 comparison group, 9 of which could target 9, 011 mRNAs; these targets were involved in 41 GO terms and 137 pathways. Comparatively, 22 up-regulated piRNAs were detected in the Ac5 vs. Ac6 comparison group, 21 of which could target 28, 969 mRNAs; these targets were engaged in 46 functional terms and 164 pathways. The results suggested the overall alteration of expression pattern of piRNAs during the developmental process of A. c. cerana larvae. Regulatory network analysis showed that piR-bmo-748815 and piR-bmo-512574 in the Ac4 vs. Ac5 comparison group as well as piR-bmo-716466 and piR-bmo-828146 in the Ac5 vs. Ac6 comparison group linked to the highest number of targets. Further investigation indicated that targets of DEpiRNAs in the above-mentioned two comparison groups could be annotated to several growth and development-associated pathways, such as Jak/STAT, TGF-{beta}, and Wnt signaling pathways, indicating the involvement of DEpiRNAs in modulating larval gut development via these crucial pathways. Moreover, the expression trends of six randomly selected DEpiRNAs were verified using a combination of stem-loop RT-PCR and RT-qPCR. These results not only provide a novel insight into the development of the A. c. cerana larval guts, but also lay a foundation for uncovering the epigenetic mechanism underlying the larval gut development.

molecular biology↗
bioRxiv2022

Pantothenate Kinase 4 Governs Lens Epithelial Fibrosis by Negatively Regulating PKM2 Related Glycolysis

Lens fibrosis is one of the leading causes of cataract in the elderly population. The primary energy substrate of the lens is glucose from the aqueous humor, and the transparency of mature lens epithelial cells (LECs) is dependent on glycolysis for ATP. Therefore, the deconstruction of reprogramming of glycolytic metabolism can contribute to further understanding of LEC epithelial-mesenchymal transition (EMT). In the present study, we found a novel pantothenate kinase 4 (PANK4)-related glycolytic mechanism that regulates LEC EMT. The PANK4 level was correlated with aging in cataract patients and mice. Loss of function of PANK4 significantly contributed to alleviating LEC EMT by upregulating pyruvate kinase M2 isozyme (PKM2), which was phosphorylated at Y105, thus switching oxidative phosphorylation to glycolysis. However, PKM2 regulation did not affect PANK4, demonstrating the downstream role of PKM2. Inhibition of PKM2 in Pank4-/- mice caused lens fibrosis, which supports the finding that the PANK4-PKM2 axis is required for LEC EMT. Glycolytic metabolism-governed hypoxia inducible factor (HIF) signaling is involved in PANK4-PKM2-related downstream signaling. However, HIF-1 elevation was independent of PKM2 (S37) but PKM2 (Y105) when PANK4 was deleted, which demonstrated that PKM2 and HIF-1 were not involved in a classic positive feedback loop. Collectively, these results indicate a PANK4-related glycolysis switch that may contribute to HIF-1 stabilization and PKM2 phosphorylation at Y105 and inhibit LEC EMT. The mechanism elucidation in our study may also shed light on fibrosis treatments for other organs.

cell biology↗
bioRxiv2022

Rapid Color Categorization in the Brain Revealed by Frequency-tagging-based EEG

The origin of color categories has been debated extensively. Historically, linguistic relativists claim that color categories are shaped by the language we speak and that color terms subsequently affect our perception of color, while universalists postulate that color categories are independent of language and formed based on perceptual mechanisms. A recent hypothesis suggests that the original fine-grained color space in the visual cortex may be transformed into categorical encoding due to top-down modulation. To test the nature of color categorization, our study adopted a sensitive frequency-tagging-based EEG paradigm where the color stimuli were presented sequentially at a fast speed of 10 Hz (SOA: 100 ms) to probe fast, implicit processing of color categories. This SOA was supposed to disrupt top-down feedbacks in visual processing. We showed that EEG responses to cross-category oddball colors at the frequency where the oddball stimuli were presented was significantly larger than the responses to within-category oddball colors. This finding suggested that the brain encodes color categories automatically when top-down feedbacks from frontoparietal areas are blocked. Our study supports the view that the categorical processing of color emerges at the early perceptual stage.

neuroscience↗
bioRxiv2022

TLR4/NF-κB Signaling Contributes to the Inflammation in Ovary and Inguinal Fats of Polycystic Ovary Syndrome

BackgroundPolycystic ovary syndrome (PCOS) is a complex reproductive endocrine disorder. It has highly heterogeneous clinical manifestations which are characterized by biochemical hyperandrogenemia, obesity, insulin resistance, dyslipidemia, anovulation, and polycystic ovaries. However, the etiologies of PCOS are still unclear. Recently, studies have found that the low-grade inflammation contributed to the occurrence of PCOS, and as a critical biomarker indicated the endocrine disruptions in PCOS. ObjectiveThis study is aimed to investigate the processes and mediators of inflammation in contributing to the development of PCOS. MethodsLetrozole (LET) induced PCOS rat model was used in this study. Body weight, body temperature, inguinal fats weight, fasting glucose level, ovarian morphology, NF-{kappa}B signaling target genes in ovary, and protein expression levels of TLR4 and NF-{kappa}B in ovarian and inguinal fats were measured in rats with placebo and LET administrations for 6 and 12 weeks. ResultsPCOS rats, especially with LET intervention for 12 weeks, had higher body weight, inguinal fats weight and fasting glucose level compared to control group. The protein expression levels of TLR4 and NF-{kappa}B in cytoplasm of ovarian and inguinal fats were increased in LET-induced PCOS rats compared to control groups, while NF-{kappa}B in nucleus were reduced in PCOS rats. The expressions of ACTB, C3, CXCL3, NQO1 and SELP in ovarian were statistically different in PCOS rats induced by LET compared to control groups. ConclusionThese findings indicated that stimulating TLR4/NF-{kappa}B pathway in inguinal fats and ovary tissues contributed to the increased inflammation in LET-induced PCOS rats, which, in turn, exacerbated the phenotype of PCOS including weight gain, adipose tissue accumulation, hyperglycemia and follicular dysplasia.

pathology↗
bioRxiv2022

Integrated single-cell sequencing analysis reveals peripheral immune landscape across the human lifespan

Systematic understanding of immune dynamics across the entire human lifespan at single-cell resolution is currently lacking. Here, we performed single-cell RNA sequencing (scRNA-seq) and single-cell T cell receptor (TCR)/B cell receptor (BCR) sequencing (scTCR/BCR-seq) on over 380,000 peripheral blood mononuclear cells collected from 45 healthy participants aged 0 to over 90 years. We revealed that the functions of T cell subsets were most susceptible to senescence among all PBMCs, featured by increased NF-{kappa}B signaling and IFN-{gamma} responses pathways, while reduced telomere maintenance and energy metabolism. We subsequently explored the rewiring of cell-cell interactions among different immune cells across the lifespan and revealed the major alteration of immune checkpoints in T cells within the cellular interaction networks. By combined analysis of scRNA-seq and scTCR-seq, we revealed that 1) GNLY+ CD8 Effector T cells exhibited a high clonal expansion with distinct functional signatures in children and the elderly; 2) Naive CD4+ T and naive CD8+ T cells displayed different aging patterns in both transcriptomes and immune repertoires; and 3) CD8+ MAIT cells showed a higher cell abundance and clonal diversity in adolescents. Furthermore, we identified a unique cytotoxic B cell subset enriched in children by scRNA-seq and scBCR-seq analysis and experimental validations. In summary, our work provided valuable insights and rich resources for understanding the development and aging of the human immune system across the lifespan.

immunology↗
bioRxiv2022

The mechanism of DNA sensor cGAS-STING regulating autophagy-related signal pathways

Cyclic GMP-AMP synthase (cGAS) serves as a DNA sensor for recognizing and binding microbial or self-DNA molecules in cells. Upon binding DNA, cGAS produces the second messenger cGAMP to activate the stimulator of interferon genes (STING), which mediates the expression of type 1 interferons (IFN-I) and other cytokines. cGAS-STING-mediated signal pathway plays an important role in innate immune reaction against microbial infections as well as autoimmunity, tumor immunology, and cellular senescence. During this process, cGAS regulates DNA damage repair and induces STING-mediated NF-{kappa}B and MAPK signal pathways in autophagy and lysosome-dependent cell apoptosis. However, the molecular mechanisms of cGAS-STING-mediated autophagy still need to be explored. Here, we found that cGAS-STING promotes autophagy by influencing multiple autophagy-related signal pathways: First, cGAS-STING promotes autophagy by inhibiting the mTOR signaling pathway; Second, cGAS-STING affects autophagy by regulating autophagy-related proteins that are also involved in cGAS-STING-mediated IFN-I and NF-{kappa}B signaling pathways; Third, the Bcl2 can interact with cGAS and STING to induce cGAS-STING-mediated up-regulation of IFN-I signaling pathway and down-regulation of NF-{kappa}B. In addition, we also found that USP19 can significantly reduce the K11-linked ubiquitination of STING in the process of autophagy. Our findings unveiled the functional role and the mechanism of cGAS-STING signaling in regulating autophagy.

molecular biology↗
bioRxiv2022

A "cooperative collaboration" between HAND2 and MYCN shapes neuroblastoma cell identity

Noradrenergic neuroblastoma (NB) is characterized by a core transcriptional regulatory circuitry (CRC) comprised of transcription factors (TFs) such as PHOX2B, HAND2 and GATA3, which form a network with MYCN. Physiological levels of MYCN mainly binds to promoters but aberrantly upregulated MYCN in NB also binds to enhancers. How MYCN invades enhancers, and what role the CRC TFs play in this process is unknown. Here we find that HAND2 assists MYCN to invade enhancers through an "indirect cooperative" TF-DNA binding mechanism. HAND2 cooperates with MYCN to compete with nucleosomes and regulate global gene transcription. The treatment of NB with an Aurora A kinase inhibitor plus HDAC inhibitor potently downregulates both MYCN and the CRC TFs and suppresses MYCN-amplified NB tumor growth. Our study identifies a "cooperative collaboration" among MYCN and CRC TFs and the simultaneous targeting these TFs is an effective way to treat this aggressive pediatric tumor.

cancer biology↗
bioRxiv2022

TransCell: In silico characterization of genomic landscape and cellular responses from gene expressions through a two-step deep transfer learning

Gene expression profiling of new or modified cell lines becomes routine today; however, obtaining comprehensive molecular characterization and cellular responses for a variety of cell lines, including those derived from underrepresented groups, is not trivial when resources are minimal. Using gene expression to predict other measurements has been actively explored; however, systematic investigation of its predictive power in various measurements has not been well studied. We evaluate commonly used machine learning methods and present TransCell, a two-step deep transfer learning framework that utilizes the knowledge derived from pan-cancer tumor samples to predict molecular features and responses. Among these models, TransCell has the best performance in predicting metabolite, gene effect score (or genetic dependency), and drug sensitivity, and has comparable performance in predicting mutation, copy number variation, and protein expression. Notably, TransCell improved the performance by over 50% in drug sensitivity prediction and achieved a correlation of 0.7 in gene effect score prediction. Furthermore, predicted drug sensitivities revealed potential repurposing candidates for new 100 pediatric cancer cell lines, and predicted gene effect scores reflected BRAF resistance in melanoma cell lines. Together, we investigate the predictive power of gene expression in six molecular measurement types and develop a web portal (http://apps.octad.org/transcell/) that enables the prediction of 352,000 genomic and cellular response features solely from gene expression profiles. Key PointsO_LIWe provide a systematic investigation on evaluating the predictive power of gene expression in six molecular measurement types including protein expression, copy number variation, mutation, metabolite, gene effect score, and drug sensitivity. C_LIO_LITransCell took advantage of the transfer learning technique, showing how to learn knowledge from the source tumors, and transfer learned weight initializations to the downstream tasks in cell lines. C_LIO_LICompared to the baseline methods, TransCell outperformed in metabolite, gene effect score, and drug sensitivity predictions. C_LIO_LITwo cases studies demonstrate that TransCell could identify new repurposing candidates for pediatric cancer cell lines as well as capture the differences of genetic dependencies in melanoma resistant cell lines. C_LI

bioinformatics↗
bioRxiv2022

Disease-modifying effects of sodium selenate in a model of drug-resistant, temporal lobe epilepsy.

There are no pharmacological disease-modifying treatments that can mitigate the seizures and comorbidities associated with established chronic temporal lobe epilepsy (TLE). This study evaluated the effect of sodium selenate in the post-status epilepticus (SE) rat model of chronic drug resistant TLE. Wistar rats underwent kainic acid-induced SE or sham. Ten-weeks post-SE, rats were randomly assigned to receive either sodium selenate, levetiracetam, or vehicle treatments continuously for 4 weeks. To evaluate the effects of the treatments, 1 week of continuous video-EEG was acquired before, during, and 4, 8 weeks post-treatment, followed by behavioral tests. Targeted and untargeted proteomics and metabolomics were performed on post-mortem brain tissue to identify potential pathways associated with modified disease outcomes. Telomere length was investigated as a novel surrogate marker of disease severity. Sodium selenate treatment was able to mitigate disease severity, reducing the number of spontaneous seizures (p< 0.05), cognitive dysfunction (p< 0.05 in both novel object placement and recognition tasks), and sensorimotor deficits (p< 0.01) 8 weeks post-treatment cessation. Moreover, increased protein phosphatase 2A (PP2A) expression, reduced hyperphosphorylated tau, and reversed telomere length shortening caused by SE (p< 0.05). Network medicine integration of multi-omics/ pre-clinical outcomes identified protein-metabolite modules positively correlated with the TLE phenotype. Our results provide evidence that treatment with sodium selenate results in a sustained disease modifying effect in chronically epileptic rats in the post-KA SE model of TLE, including improved comorbid learning and memory deficits.

neuroscience↗
bioRxiv2022

PRMT5 is a therapeutic target in choroidal neovascularization

Ocular neovascular diseases including neovascular age-related macular degeneration (nvAMD) are widespread causes of blindness. Patients non-responsiveness to currently used biologics that target vascular endothelial growth factor (VEGF) poses an unmet need for novel therapies. Here, we identify protein arginine methyltransferase 5 (PRMT5) as a novel therapeutic target for nvAMD. PRMT5 is a well-known epigenetic enzyme. We previously showed that PRMT5 methylates and activates a proangiogenic and proinflammatory transcription factor, the nuclear factor kappa B (NF-{kappa}B), which has a master role in tumor progression, notably in pancreatic ductal adenocarcinoma and colorectal cancer. We identified a potent and specific small molecule inhibitor of PRMT5, PR5-LL-CM01, that dampens the methylation and activation of NF-{kappa}B. Here for the first time, we assessed the antiangiogenic activity of PR5-LL-CM01 in ocular cells. Immunostaining of human nvAMD sections revealed that PRMT5 is highly expressed in the retinal pigment epithelium (RPE)/choroid where neovascularization occurs, while mouse eyes with laser induced choroidal neovascularization (L-CNV) showed PRMT5 is overexpressed in the retinal ganglion cell layer and in the RPE/choroid. Importantly, inhibition of PRMT5 by PR5-LL-CM01 or shRNA knockdown of PRMT5 in human retinal endothelial cells (HRECs) and induced pluripotent stem cell (iPSC)-derived choroidal endothelial cells (iCEC2) reduced NF-{kappa}B activity and the expression of its target genes, such as tumor necrosis factor (TNF-) and VEGF-A. In addition to inhibiting angiogenic properties of proliferation and tube formation, PR5-LL-CM01 blocked cell cycle progression at G1/S-phase in a dose-dependent manner in these cells. Thus, we provide the first evidence that inhibition of PRMT5 impedes angiogenesis in ocular endothelial cells, suggesting PRMT5 as a potential therapeutic target to ameliorate ocular neovascularization.

pharmacology and toxicology↗
bioRxiv2022

Graph deep learning reveals multiple signal pathways activated in anti-citrullinated protein antibodies stimulated synoviocytes

AO_SCPLOWBSTRACTC_SCPLOWWe present a study of anti-citrullinated protein antibodies stimulated fibroblast-like synoviocytes from patients with rheumatoid arthritis, which is powered by a novel graph deep learning framework applied to single-cell mRNA expression data. This new analytical framework discovered dominant pathways that suggest IL1-IL1R mediated signaling, a novel signal transduction response to ACPA-stimulation, and comfirmed our previous finding of PI3K/AKT activation in response of ACPA-stimulation as well. The study demonstrated the capability of graph deep learning framework on signaling pathway analysis. The findings suggest that ACPAs contribute to distinct pathogenic events through activating multiple signaling pathways.

molecular biology↗
bioRxiv2022

Preferred synonymous codons are translated more accurately: Proteomic evidence, among-species variation, and mechanistic basis

A commonly stated cause of the widespread phenomenon of unequal uses of synonymous codons is their differential translational accuracies. However, this long-standing translational accuracy hypothesis (TAH) of codon usage bias has had no direct evidence beyond anecdotes. Analyzing proteomic data from Escherichia coli, we observe higher translational accuracies of more frequently used synonymous codons, offering direct, global evidence for the TAH. The experimentally measured codon-specific translational accuracies validate a sequence-based proxy; this proxy provides support for the TAH from the vast majority of over 1000 taxa surveyed in all domains of life. We find that the relative translational accuracies of synonymous codons vary substantially among taxa and are strongly correlated with the amounts of cognate tRNAs relative to those of near-cognate tRNAs. These and other observations suggest a model in which selections for translational efficiency and accuracy drive codon usage bias and its coevolution with the tRNA pool.

genetics↗
bioRxiv2022

Impact of Nosema ceranae invasion on sucrose solution consumption, midgut epithelial cell structure, and lifespan of Apis cerana cerana workers

Nosema ceranae is an intracellular fungal parasite for honeybees, leading to chronic disease named bee nosemosis with worldwide distribution. Asian honeybee (Apis cerana) is the original host for N. ceranae, but the impact of N. ceranae infection on A. cerana physiology is largely unknown. In this current work, workers of Apis cerana cerana, a subspecies of Asian honeybee, were artificially inoculated with N. ceranae spores and reared under lab conditions, followed by detection of fungal spore load as well as host sucrose solution consumption, midgut epithelial cell structure, and lifespan. The result of spore counting suggested that the spore load in the host midgut decreased significantly during 1 dpi-2 dpi, whereas that displayed an elevated trend among 2 dpi-13 dpi. The sucrose solution consumption of workers in N. ceranae-inoculated groups among 1 dpi-20 dpi was always higher than that of workers in un-inoculated groups; additionally, the difference of sucrose solution consumption between these two groups at 4 dpi, 5 dpi, and 13 dpi was of significance. Based on microscopic observation of paraffin sections, darkly stained parasites were clearly detected in the midgut epithelial cells of N. ceranae-inoculated workers at 7 dpi-10 dpi, whereas no parasite was observed in those of un-inoculated workers. In addition, the boundaries of un-inoculated host epithelial cells were intact and the darkly stained nucleus were clear, while the boundaries of midgut epithelial cells of N. ceranae-inoculated workers were blurred, the nucleus were almost disappeared, and the nucleic acid substances were diffused. Moreover, the survival rates of workers in both N. ceranae-inoculated groups and un-inoculated groups at 1 dpi-5 dpi were pretty high and then started to decrease at 5 dpi; the survival rate of workers in N. ceranae-inoculated groups was always lower than that in un-inoculated groups, with significant difference between these two groups during 11 dpi-20 dpi. These results together indicate that the quantity of fungal spores continuously elevated with the microsporidian multiplication, causing energetic stress for workers and host cell structure damage, which further negatively affected the host lifespan. Our findings offer a solid basis not only for exploring the molecular mechanism underlying N. ceranae infection but also for investigating the interaction between N. ceranae and eastern honeybee.

molecular biology↗
bioRxiv2021

The role of antigen recognition in the γδ T cell response at the controlled stage of M. tuberculosis infection.

{gamma}{delta} T cells contribute to host immune defense uniquely; but how they function in different stages (e.g., acute versus chronic) of a specific infection remains unclear. As the role of{gamma}{delta} T cells in early, active Mycobacterium tuberculosis (Mtb) infection is well documented, we focused on elucidating the{gamma}{delta} T cell response in persistent or controlled Mtb infection. Systems analysis of circulating{gamma}{delta} T cells from a South African adolescent cohort identified a distinct population of CD8+{gamma}{delta} T cells that expanded in this state. These cells had features indicative of persistent antigenic exposure but were robust cytolytic effectors and cytokine/chemokine producers. While these{gamma}{delta} T cells displayed an attenuated response to TCR-mediated stimulation, they expressed Natural Killer (NK) cell receptors and had robust CD16 (Fc{gamma}RIIIA)-mediated cytotoxic response, suggesting alternative ways for{gamma}{delta} T cells to control this stage of the infection. Despite this NK- like functionality, the CD8+{gamma}{delta} T cells consisted of highly expanded clones, which utilized TCRs with different V{gamma}/{delta} pairs. Theses TCRs could respond to an Mtb-lysate, but not to phosphoantigens, which are components of Mtb-lysate that activate{gamma}{delta} T cells in acute Mtb infection, indicating that the CD8+{gamma}{delta} T cells were induced in a stage-specific, antigen-driven manner. Indeed, trajectory analysis showed that these{gamma}{delta} T cells arose from naive cells that had traversed distinct differentiation paths in this infection stage. Importantly, increased levels of CD8+{gamma}{delta} T cells were also found in other chronic inflammatory conditions, including cardiovascular disease and cancer, suggesting that persistent antigenic exposure may lead to similar{gamma}{delta} T cell responses.

immunology↗
bioRxiv2021

High-resolution mapping of the period landscape reveals polymorphism in cell cycle frequency tuning

Many biological oscillators exhibit widely tunable frequency in adapting to environmental changes. Although theoretical studies have proposed positive feedback as a mechanism underlying an oscillators large tunability, there have been no experiments to test it. Here, applying droplet microfluidics, we created a population of synthetic cells, each containing a cell-cycle oscillator and varying concentrations of cyclin B mRNAs for speed-tuning and positive-feedback inhibitors for modulating network interactions, allowing a continuous mapping of the cell-cycle period landscape in response to network perturbation. We found that although the cell cycles high tunability to cyclin B can reduce with Wee1 inhibition, the reduction is not as great as theoretically predicted, and another positive-feedback regulator, PP2A, may provide additional machinery to ensure the robustness of cell cycle period tunability. Remarkably, we discovered polymorphic responses of cell cycles to the PP2A inhibition. Droplet cells display a monomodal distribution of oscillations peaking at either low or high PP2A activity or a bimodal distribution with both low and high PP2A peaks. We explain such polymorphism by a model of two interlinked bistable switches of Cdk1 and PP2A where cell cycles exhibit two different oscillatory modes in the absence or presence of PP2A bistability.

systems biology↗