Biology subjects

Yi, M.

Publications and source records attributed to Yi, M..

18 recordsLinked to original sources

bioRxiv2026

Increased chromatin accessibility following 1α,25-dihydroxyvitamin D3 treatment in human endometrial stromal cells

Vitamin D signaling has recognized roles in female reproductive physiology, but its effects at the chromatin level in endometrial stromal cells are still unclear. Here, we investigated how the active form of vitamin D, 1,25-dihydroxyvitamin D3, or calcitriol, influences the accessible chromatin landscape of human endometrial stromal cells. Assay for transposase-accessible chromatin using sequencing (ATAC-seq) was performed on T-HESCs treated with either a vehicle or 1,25(OH)2D3. Ligand treatment increased overall chromatin accessibility, shown by higher ATAC-seq signal intensity, while causing only minor changes in the total number of called peaks. Peak annotation revealed that accessible regions were spread across both promoter-proximal and distal genomic areas. Integrating this data with CUT&RUN and RNA sequencing showed that most vitamin D-responsive cistromic modifications and transcripts were linked to nearby open chromatin, though fewer were associated with regions that were significantly differentially accessible. These results suggest that 1,25(OH)2D3-dependent transcription mainly occurs within a permissive, pre-accessible chromatin environment. This study offers new evidence that active vitamin D influences the epigenomic landscape of human endometrial stromal cells, establishing the chromatin-based molecular response to a chemically-defined VDR ligand, 1,25(OH)2D3, relevant to stromal differentiation and preparation for decidualization. HighlightsO_LIFirst evidence suggesting the direct impact of active vitamin D, 1,25-dihydroxyvitamin D3, 1,25(OH)2D3, enhanced the signal intensity of chromatin accessibility in human endometrial stromal cells C_LIO_LIMost accessible chromatin regions were shared between vehicle and ligand-treated human endometrial stromal cells C_LIO_LI1,25(OH)2D3-responsive transcription occurs largely within pre-accessible chromatin in human endometrial stromal cells C_LIO_LIAssay for transposase-accessible chromatin sequencing (ATAC-seq) defines a chromatin-level pharmacologic response to a chemically defined VDR ligand in human endometrial stromal cells C_LI

molecular biology↗

bioRxiv2026

Myeloid CD209 impairs T-cell activation by inducing ICAM-2-ERM-dependent cortical stiffening

Resistance to PD-1-based immunotherapy remains a major challenge in cancer treatment, especially in immunologically "cold" tumors characterized by T-cell exclusion and impaired effector function. Tumor-associated myeloid cells are important mediators of this resistance, but whether they directly suppress T-cell immunity through mechanical regulation remains unclear. Here, we identify DC-SIGN (CD209), a myeloid-expressed C-type lectin receptor, as a mechanosuppressive regulator of antitumor T-cell immunity. DC-SIGN is selectively enriched in tumor-infiltrating M2-like macrophages and monocytes, and its expression is associated with poor clinical response to PD-1 blockade and elevated TIDE scores across multiple cancer types. Mechanistically, DC-SIGN directly engages ICAM-2 on T cells and activates ROCK1-ERM signaling. This interaction increases T-cell cortical stiffness, destabilizes T cell-antigen-presenting cell interactions, and attenuates T-cell receptor signaling. Blocking the DC-SIGN-ICAM-2-ERM pathway restores T-cell activation and promotes CD8+ T-cell infiltration and effector function in mouse, humanized, and ex vivo human tumor systems. Importantly, DC-SIGN blockade overcomes resistance to PD-1-based immunotherapy in refractory and immunologically "cold" tumor models, and further enhances the response to PD-1 inhibition. Together, our findings define a myeloid-derived mechanical immune checkpoint and reveal T-cell mechanosuppression as a targetable mechanism of tumor immune evasion and immunotherapy resistance.

immunology↗

bioRxiv2025

Adipocyte-related genes analysis contributes to the prognosis of atrial fibrillation

BackgroundPatients with mild left atrial appendage fibrosis have a significantly lower rate of atrial fibrillation (AF) recurrence after 5 years compared to those with moderate or severe fibrosis, which presented a significantly increased positive area of cellular senescence. MethodsGSE135445, a RNA-sequencing dataset between epicardial adipose tissue (EAT) from patients with persistent non-valvular AF and sinus rhythm (SR), was downloaded and analyzed and hub genes were obtained. To obtain the abundance of immune cells, the CIBERSORT algorithm with 100 permutations was applied. The senescent hub genes were obtained and validated using human blood samples. ResultsA total of 164 up-regulated and 317 down-regulated DEGs was obtained between EAT from subjects with AF and SR. Using immune infiltration analysis in whole PAT related DEGs, the abundance of M0 macrophages was significantly different between PAT and SAT and 22 M0 macrophages-related DEGs were also obtained, such as MMP7, APOE, CCND1, MMP12 and APOC1. Venn diagram was utilized to obtain the same transcripts between senescence datasets and DEGs and PPI network was used to 94 overlapping genes. The top15-degree senescence adipicytes hub genes were explored. To investigate senescence-related hub genes effects on AF progression, we collected the blood samples of patients with paroxysmal atrial fibrillation and persistent atrial fibrillation. There were no significant differences at baseline characteristics and laboratory examinations at 1d after admission except heart failure history and function examinations, for instance, ALT, LDL, LVEF and LA diameters. Using univariate analysis and multivariate analysis, heart failure history, ALT and LA diameters can be prognostic factors for AF progression. BMP7, COL4A3, COL4A4, CHRD, IRX1, SPON1, ALPL, TCF19 and SIX2 were validated to be highly expressed in persistent atrial fibrillation compared to paroxysmal atrial fibrillation. ConclusionBased on our current study, BMP7, COL4A3, COL4A4, CHRD, IRX1, SPON1, ALPL, TCF19 and SIX2 were validated to be highly expressed in persistent atrial fibrillation compared to paroxysmal atrial fibrillation, which may be potential therapeutic targets to treat AF progression and improve patients prognosis.

genetics↗

bioRxiv2025

Impact of vitamin D deficiency on defective endometrial decidualization and the repressive role of vitamin D receptor (VDR) in the epigenomic network

Identifying the factors that regulate female reproduction is crucial to understanding how the environment affects female reproductive health. The vitamin D receptor (VDR) and its ligands (primarily 1,25(OH)2D3) have a recognized role in calcium homeostasis; however, their broader impact on female reproduction remains underexplored. We demonstrate that the VDR and its ligands are involved in the hormonal induction of uterine decidualization. Mice fed a vitamin D-deficient diet displayed an impaired hormonally induced decidual response. In a human telomerase reverse transcriptase-immortalized human endometrial stromal cell line (T-HESC), VDR decreased during in vitro decidualization. Small interfering RNA (siRNA) knockdown of VDR in T-HESC enhanced in vitro decidualization, while overexpression of VDR inhibited it. Chromatin accessibility and histone modification analyses revealed that VDR functions as a chromatin regulator, restricting accessibility and repressing transcription in specific genomic regions. Transcriptomic analyses confirmed that VDR broadly modulates gene expression, with most ligand-mediated effects occurring through the VDR. These findings identify VDR as a key regulator of transcriptional and chromatin landscapes in human endometrial stromal cells, offering novel insights into vitamin D signaling in reproduction. This study highlights the potential of targeting vitamin D pathways to treat uterine disorders associated with impaired decidualization and reduced fertility. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=80 SRC="FIGDIR/small/688535v2_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@6b048org.highwire.dtl.DTLVardef@11f7b4corg.highwire.dtl.DTLVardef@1d7dbfaorg.highwire.dtl.DTLVardef@ab3894_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2025

Psilocybin Prolongs the Neurovascular Coupling Response in Mouse Visual Cortex

Psilocybin has profound therapeutic potential for various mental health disorders, but its mechanisms of action are unknown. Functional MRI studies have reported the effects of psilocybin on brain activity and connectivity; however, these measurements rely on neurovascular coupling to infer neural activity changes and assume that blood flow responses to neural activity are not altered by psilocybin. Using two-photon excited fluorescence imaging in the visual cortex of awake mice to simultaneously measure neural activity and capillary blood flow dynamics, we found that psilocybin administration prolonged the increase in visual stimulus-evoked capillary blood flow - an effect which was reduced by pretreatment with a 5-HT2AR antagonist - despite not causing changes in the stimulus-evoked neural response. Multi-modal widefield imaging also showed that psilocybin extends the stimulus-evoked vascular responses in surface vessels with no observed effect on the population neural response. Computational simulation with a whole-brain neural mass model showed that prolonged neurovascular coupling responses can lead to spurious increases in BOLD-based measures of functional connectivity. Together, these findings demonstrate that psilocybin broadens neurovascular responses in the brain and highlights the importance of accounting for these effects when interpreting human neuroimaging data of psychedelic drug action.

neuroscience↗

bioRxiv2025

Circulating tumor cell heterogeneity and MMP9 expression in clinical correlation with breast cancer

ObjectivesThis study aimed to investigate the association between the heterogeneity of circulating tumor cell (CTC) subtypes and the expression patterns of matrix metalloproteinase 9 (MMP9) with clinicopathological parameters in breast cancer patients. The distribution of CTC subtypes, MMP9 expression levels, and their influence on tumor progression. MethodsA total of 303 breast cancer patients were enrolled in this study. The association between CTCs subtypes in peripheral blood, MMP9 expression and clinical or pathological data of patients were analyzed. ResultsThe number of mesenchymal CTCs increased significantly with the number of lymph node metastases (P < 0.05), and high MMP9 expression was positively correlated with lymph node involvement (P < 0.05). The proportion of intermediate to high MMP9 expression was significantly higher in mixed CTCs compared to epithelial and mesenchymal CTCs (P < 0.05). High MMP9 expression in tumor tissues was associated with increased CTCs production and induction of epithelial-mesenchymal transition (EMT) (P < 0.05), as well as an elevated number of MMP9-positive CTCs (P < 0.05). ConclusionsThese findings suggest that MMP9 is positively associated with CTCs production and EMT process, and MMP9 may contribute to tumor metastasis by promoting CTC shedding and EMT by degrading the extracellular matrix. We recommend compliance with the Mesh guidelines: https://www.ncbi.nlm.nih.gov/mesh/

cancer biology↗

bioRxiv2025

Pathogenic strains of a gut commensal drive systemic platelet activation and thromboinflammation in lupus nephritis

Imbalances in the gut microbiome have been linked to increased intestinal permeability and disease flares in systemic lupus erythematosus (SLE). Our study revealed that patients with flares of lupus nephritis (LN) and intestinal expansions of the anaerobic commensal, Ruminococcus gnavus (RG), displayed whole blood transcriptome profiles indicative of platelet, neutrophil, and myeloid cell activation, a profile reminiscent of sepsis. Serum analysis confirmed elevated serum levels of Platelet Factor 4 and neutrophil extracellular traps, which significantly correlated with levels of IgG-antibody to a novel lipoglycan (LG) produced by pathogenic RG strains, which was also documented in an independent LN cohort. To test for causality, in vivo mouse models further demonstrated that gut colonization with LG-producing RG strains, as well as a single intraperitoneal challenge with an LG preparation, caused platelet activation and megakaryocytosis in bone marrow and spleen. Mice colonized with RG strains that produce LG developed cellular infiltration of the kidneys by neutrophils and monocytes. Hence, RG expansions during renal flares may identify a specific LN flare endotype driven by thromboinflammatory mechanisms. Antibodies that arise from immune exposure to the RG lipoglycan may serve as a surrogate biomarker, helping to elucidate the impact of the relationship between gut microbiota communities and clinical outcomes in patients afflicted by LN. [208] Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=164 SRC="FIGDIR/small/641288v1_ufig1.gif" ALT="Figure 1"> View larger version (74K): org.highwire.dtl.DTLVardef@1239f8eorg.highwire.dtl.DTLVardef@1c062caorg.highwire.dtl.DTLVardef@195ece2org.highwire.dtl.DTLVardef@1f3123f_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

A large-scale foundation model for bulk transcriptomes

Large language models (LLMs) have emerged as powerful foundation models leading to breakthroughs in transcriptome analysis. However, current RNA-seq foundation models are exclusively pretrained on sparse single-cell RNA-seq (scRNA-seq) data, which typically detects only [~]3000 genes per cell. This thus creates a critical gap in models specifically designed for bulk transcriptomes, a fundamentally different modality capable of profiling [~]16,000 genes per sample. Here we propose BulkFormer, a large-scale foundation model for bulk transcriptome analysis. With 150 million parameters covering about 20,000 protein-coding genes, BulkFormer is pretrained on over 500,000 human bulk transcriptomic profiles. BulkFormer incorporates a hybrid encoder architecture, combining a graph neural network to capture explicit gene-gene interactions and a performer module to model global expression dependencies. As a result, despite incurring much lower training costs than scRNA-seq foundation models, BulkFormer consistently outperforms them in all six downstream tasks: transcriptome imputation, disease annotation, prognosis modeling, drug response prediction, compound perturbation simulation, and gene essentiality scoring. Notably, BulkFormer not only enhances the discovery of novel clinical biomarkers but also uncovers latent disease mechanisms by imputing biologically meaningful gene expression. Collectively, these results demonstrate BulkFormers power as a versatile and robust framework for bulk transcriptome modeling and biomedical discovery, bridging a critical gap in the current foundation model landscape.

bioinformatics↗

bioRxiv2025

Nervous Necrosis Virus Capsid Protein Functions as a SUMO E3 Ligase to Activate MAVS-Dependent NF-κB Signaling

Nervous necrosis virus (NNV) is a lethal aquatic pathogen that activates NF-{kappa}B signaling to manipulate host immune responses, yet the underlying molecular mechanisms remain poorly defined. Here, we identify the NNV capsid protein (CP) as a novel viral SUMO E3 ligase that promotes SUMOylation of Lateolabrax japonicus mitochondrial antiviral signaling protein (MAVS) to drive NF-{kappa}B activation. We show that CP induces p65 nuclear translocation and upregulates proinflammatory cytokine expression in a MAVS-dependent manner. Mechanistically, CP interacts with SUMO2 and the E2 conjugating enzyme L. japonicus UBC9 to promote MAVS SUMOylation at lysine 325 (K325), which stabilizes MAVS, facilitates its aggregation, and amplifies downstream NF-{kappa}B signaling. Notably, disruption of this modification via the K325R mutation or SUMOylation inhibition abrogates MAVS aggregation and inflammatory responses. Our findings reveal a previously unrecognized strategy by which NNV hijacks the host SUMOylation machinery to fine-tune MAVS function, promoting immune evasion and viral persistence. SummaryNervous necrosis virus (NNV) is a highly pathogenic virus in aquatic animals that manipulates host immune signaling to promote infection. Here, we identify the NNV capsid protein (CP) as a viral SUMO E3 ligase that modifies the mitochondrial antiviral signaling protein MAVS via SUMOylation at lysine 325. This modification enhances MAVS stability and aggregation, leading to robust activation of the NF-{kappa}B signaling pathway and increase expression of proinflammatory cytokines. Disruption of this modification abolishes CP-mediated immune activation. This study unveils a previously unrecognized mechanism by which NNV exploits host SUMOylation machinery to modulate MAVS function, contributing to immune evasion and facilitating viral persistence. These findings provide valuable insights into virus-host interactions and highlight potential therapeutic targets against NNV infections.

microbiology↗

bioRxiv2024

Myosin light chain 3 serves as a receptor for nervous necrosis virus entry into host cells via the macropinocytosis pathway

Nodaviridae infections cause severe mortality in insects and fish, with nervous necrosis virus (NNV) posing significant threats to global fish populations. However, the host factors involved in NNV entry remain poorly understood. We identify myosin light chain 3 from marine medaka (Oryzias melastigma) (MmMYL3) as a novel receptor for red-spotted grouper NNV (RGNNV), facilitating internalization via macropinocytosis. MmMYL3 directly binds the RGNNV capsid protein (CP), which dependents on the arm and S domains of CP and the EF-hand2 domain of MmMYL3. In vitro experiments showed that MmMYL3 siRNA, protein, anti-MYL3 antibodies or the arm domain synthetic peptides blocked RGNNV entry. Moreover, in vivo administration of MmMYL3 protein also inhibited RGNNV infection. Ectopic MmMYL3 expression enabled RGNNV internalization into resistant cells. Notably, MmMYL3 facilitated RGNNV internalization through the macropinocytosis pathway via the IGF1R-Rac1/Cdc42 axis. Collectively, our findings underscore MYL3s crucial role in NNV entry and its potential as an antiviral target.

microbiology↗

bioRxiv2024

The long noncoding RNA lnc-FANCI-2 restricts RAS signaling and phosphorylation of Akt and Erk in HPV16-infected cervical cancer cells

We recently discovered the expression of a long noncoding RNA, lnc-FANCI-2, coinciding with cervical lesion progression from CIN1, CIN2-3 to cervical cancer. Viral E7 of high-risk HPVs and host transcription factor YY1 are two major factors promoting lnc-FANCI-2 expression. To explore possible roles of lnc-FANCI-2 in HPV-induced cervical carcinogenesis, we ablated the expression of lnc-FANCI-2 in the HPV16-positive cervical cancer cell line, CaSki. Knock-out (KO) single cell clones expressed HPV16 oncogenes normally but displayed altered cell morphology and proliferation when compared with the parental cells. Proteomic profiling of cytosolic and secreted proteins from the parental and KO cells showed that lnc-FANCI-2 regulates expression of a subset of cell soluble receptors responsible for cell signaling, epithelial mesenchymal transition, and IFN responses. RNA-seq analyses revealed that, relative to the parental cells, lnc-FANCI-2 KO cells exhibited significantly increased RAS signaling but decreased IFN pathways. In the KO cells, phosphorylated Akt and Erk1/2, two important RAS pathway effectors, were increased more than 3-fold, accompanied by increase of IGFBP3, MCAM, VIM, and CCND2 (cyclin D2) and decrease of RAC3 expression. High levels of lnc-FANCI-2 and lower levels of MCAM in cervical cancer patients are associated with improved survival. We found that lnc-FANCI-2 interacts specifically with 32 host proteins, including H13, HNRH1, K1H1, MAP4K4, and RNPS1, and knockdown of MAP4K4 in CaSki cells led to an increase of phosphorylation of Erk1/2 and somewhat Akt. In summary, a key function of lnc-FANCI-2 is to intrinsically regulate RAS signaling to impact cervical lesion progression and affect cervical cancer prognosis. SignificanceExpression of lnc-FANCI-2 is related to cervical lesion progression. Knock-out (KO) or knock-down (KD) of lnc-FANCI-2 expression in HPV16-positive cervical cancer cells CaSki significantly increases RAS signaling, phosphorylation of Akt and Erk1/2, and the epithelial mesenchymal transition factors. lnc-FANCI-2 KO also regulates the expression of a subset of cell soluble receptor proteins IGFBP3 and MCAM. A high level of lnc-FANCI-2 and lower level of MCAM in cervical cancer patients are associated with improved survival. lnc-FANCI-2 in CaSki cells interacts specifically with 32 host proteins, including MAP4K4. KD of MAP4K4 expression in CaSki cells led to an increase in phosphorylation of Erk1/2 and Akt. Thus, one lnc-FANCI-2 function is to intrinsically regulate RAS signaling to impact cervical lesion progression.

cancer biology↗

bioRxiv2024

Feedback loop regulation between viperin and viral hemorrhagic septicemia virus through competing protein degradation pathways

Viperin is an antiviral protein that exhibits a remarkably broad spectrum of antiviral activity. Viperin-like proteins are found all kingdoms of life, suggesting it is an ancient component of the innate immune system. However, viruses have developed strategies to counteract viperins effects. Here, we describe a feedback loop between viperin and viral hemorrhagic septicemia virus (VHSV), a common fish pathogen. We show that Lateolabrax japonicus viperin (Ljviperin) is induced by both IFN-independent and IFN-dependent pathways, with the C-terminal domain of Ljviperin being important for its anti-VHSV activity. Ljviperin exerts an antiviral effect by binding both the nucleoprotein (N) and phosphoprotein (P) of VHSV and induces their degradation through the autophagy pathway, which is an evolutionarily conserved antiviral mechanism. However, counteracting viperins activity, N protein targets and degrades transcription factors that up-regulate Ljviperin expression, interferon regulatory factor (IRF) 1 and IRF9, through ubiquitin-proteasome pathway. Together, our results reveal a previously unknown feedback loop between viperin and virus, providing potential therapeutic targets for VHSV prevention. ImportanceViral hemorrhagic septicaemia (VHS) is a contagious disease caused by the viral hemorrhagic septicaemia virus (VHSV), which poses a threat to over 80 species of marine and freshwater fish. Currently, there are no effective treatments available for this disease. Understanding the mechanisms of VHSV-host interaction is crucial for preventing viral infections. Here, we found that, as an ancient antiviral protein, viperin degrades the N and P proteins of VHSV through the autophagy pathway. Additionally, the N protein also impacts the biological functions of IRF1 and IRF9 through the ubiquitin-proteasome pathway, leading to the suppression of viperin expression. Therefore, the N protein may serve as a potential virulence factor for the development of VHSV vaccines and screening of antiviral drugs. Our research will serve as a valuable reference for the development of strategies to prevent VHSV infections.

immunology↗

bioRxiv2022

Ring-finger protein 34 facilitates nervous necrosis virus evading antiviral innate immunity by targeting TBK1 and IRF3 for ubiquitination and degradation

Ubiquitination, as one of the most prevalent posttranslational modifications of proteins, enables a tight control on host immune responses. Many viruses hijack the host ubiquitin system to regulate host antiviral responses for their survival. Here, we found that fish pathogen nervous necrosis virus (NNV) recruited an E3 ubiquitin ligase ring finger protein 34 (RNF34) to inhibit RLRs-mediated interferons (IFN) response via ubiquitinating TBK1 and IRF3. Ectopic expression of RNF34 greatly enhances NNV replication and prevents IFN production, while deficiency of RNF34 led to the opposite effect. Furthermore, RNF34 targets TBK1 and IRF3 via its RING domain. Of note, the interactions between RNF34 and TBK1 or IRF3 were conserved in different fish species. Mechanically, RNF34 promote K27-linked ubiquitination and degradation of TBK1 and IRF3, which in turn diminishing TBK1-induced translocation of IRF3 from cytoplasm to nucleus. Ultimately, NNV capsid protein (CP) was found directly bind with RNF34 and this interaction was conserved in different fishes, and CP induced TBK1 and IRF3 degradation and IFN suppression was depended on RNF34. Our finding demonstrated a novel mechanism by which NNV CP evaded host innate immunity via RNF34, and provided a potential drug target for the control of NNV infection. Author SummaryUbiquitination plays an essential role in the regulation of innate immune responses to pathogens. NNV, a kind of RNA virus, is the causal agent of a highly destructive disease in a variety of marine and freshwater fish. Previous study reported NNV could hijack the ubiquitin system to manipulate the hosts immune responses, however, how NNV utilizes ubiquitination to facilitate its own replication is not well understood. Here, we identified a novel distinct role of E3 ubiquitin ligase RNF34 as an IFN antagonist to promote NNV infection. Nervous necrosis virus capsid protein utilized RNF34 to target TBK1 and IRF3 for K27 and K48-linked ubiquitination degradation. Importantly, the interactions between RNF34 and CP, TBK1 or IRF3 are conserved in different fishes, suggesting it is a general immune evasion strategy exploited by NNV to target the IFN response via RNF34.

immunology↗

bioRxiv2022

A novel inovirus reprograms metabolism and motility of marine Alteromonas

Members from the Inoviridae family with striking features are widespread, highly diverse and ecologically pervasive across multiple hosts and environments; however, very small amount of inoviruses have been isolated and studied. Here, a filamentous phage infecting Alteromonas abrolhosensis, designated {phi}AFP1, was isolated from the South China Sea and represented as a novel genus of Inoviridae. {phi}AFP1 consisted of a single-stranded DNA genome (5986 bp), encoding eight putative ORFs. Comparative analyses revealed {phi}AFP1 could be regarded as genetic mosaics, which especially came from Ralstonia and Stenotrophomonas phages. The temporal transcriptome analysis of A. abrolhosensis to {phi}AFP1 infection reveals that 7.78% of the host genes were differentially expressed. The genes involved in translation processes, ribosome pathways and degradation of multiple amino acid pathways at plateau period were upregulated, while host material catabolic and bacterial motility-related genes were downregulated, indicating that {phi}AFP1 might hijack the energy of the host for the synthesis of phage proteins. {phi}AFP1 exerted the step-by-step control on host genes through the appropriate level of the utilizing host resources, affirming a new non-standard regulatory strategy of viral temperately control over the host transcriptional profile. Our study provides novel information for a better understanding of filamentous phage characteristics and phage-host interactions.

microbiology↗

bioRxiv2021

Overexpression of SHORT-ROOT2 transcription factor enhanced the outgrowth of mature axillary buds in poplar trees

O_LIPlant branching is usually prevented by an actively proliferating apex. In poplars, one GRAS family member, SHORT-ROOT2 (PtSHR2), was preferentially expressed in axillary buds (AXBs) and was inducible during bud maturation and activation. Overexpression of PtSHR2 (PtSHR2OE) in hybrid poplar impaired the apical dominance and simultaneously promoted the outgrowth of axillary branches below the maturation point (BMP), accompanied by regulated expression of genes critical for axillary meristem initiation and bud formation. C_LIO_LIFollowing a detained phenotypic characterization, we compared the IAA and trans-zeatin levels in apical shoots and AXBs of wild-type and PtSHR2OE trees, together with gene expression analyses and defoliation, decapitation, and hormone reapplication assays. C_LIO_LIPtSHR2OE AXBs contained a significantly lower ratio of auxin to cytokinin than wild-type AXBs, particularly in those below the BMP. Decapitation induced a faster bud burst in PtSHR2OE trees than in wild-type plants, and it could be strongly inhibited by exogenously applied auxin and cytokinin biosynthesis inhibitor, but only partially inhibited by N-1-naphthylphthalamic acid (NPA). C_LIO_LIAn impaired basipetal auxin transport, rather than an insufficient auxin biosynthesis or auxin insensitivity, disturbed the local hormonal homeostasis in PtSHR2OE AXBs, which in turn enhanced the axillary bud initiation and promoted the bud release. C_LI HighlightOverexpression of PtSHR2 in poplar impaired the apical dominance and promoted axillary bud outgrowth below the maturation point through disturbing the basipetal auxin transport and auxin and cytokinin homeostasis.

genetics↗

bioRxiv2021

Thiophosphopeptides Instantly Targeting Golgi Apparatus and Selectively Killing Cancer Cells

Golgi apparatus is emerging as a key signaling hub of cells, but there are few approaches for targeting Golgi and selectively killing cancer cells. Here we show an unexpected result that changing an oxygen atom of the phosphoester bond in phospho-peptides by a sulfur atom enables instantly targeting Golgi apparatus (GA) and selectively killing cancer cells by enzymatic self-assembly. Specifically, conjugating cysteamine S-phosphate to the C-terminal of a self-assembling peptide generates a thiophospho-peptide. Being a substrate of alkaline phosphatase (ALP), the thiophosphopeptide undergoes rapid ALP-catalyzed dephosphorylation to form a thiopeptide that self-assembles. The thiophosphopeptide enters cells via caveolin-mediated endocytosis and macropinocytosis and instantly accumulates in GA because of dephosphorylation and formation of disulfide bonds in Golgi. Moreover, the thiophosphopeptide, targeting Golgi, potently and selectively inhibits cancer cells (e.g., HeLa) with the IC50 (about 3 M), which is an order of magnitude more potent than that of the parent phosphopeptide. This work, as the first report of thiophospho-peptide for targeting Golgi, illustrates a new molecular platform for designing enzyme responsive molecules that target subcellular compartment for functions.

biochemistry↗

bioRxiv2019

Multispectral Imaging Differentiates Unique Macrophage Profiles in Patients with Distinct Chronic Liver Diseases

Intrahepatic macrophages influence the composition of the microenvironment, host immune response to liver injury, and development of fibrosis. Compared to stellate cells, the role of intrahepatic macrophages in the development of fibrosis remains ill defined. Multispectral imaging allows detection of multiple markers in situ in human formalin-fixed, paraffin-embedded tissue. This cutting-edge technology is ideal for analyzing human liver tissues since it allows spectral unmixing of fluorophore signals, subtraction of auto-fluorescence, and preserves architecture and the in vivo hepatic milieu. We analyzed resident Kupffer cells (CD68+), monocyte-derived macrophages (Mac387+), pro-fibrogenic macrophages (CD163+), and co-expression of pro-inflammatory (CD14) and anti-inflammatory (CD16) markers in liver biopsies from patients with hepatitis C virus (HCV) and different stages of fibrosis. Liver biopsies with advanced fibrosis showed increased accumulation of CD163+, MAC387+ and CD68+ macrophages in the portal tracts when compared to those with minimal fibrosis. Imaging software generated t-distributed stochastic neighbor embedding (t-SNE) plots and phenotype matrices that facilitated comparison of macrophage profiles. These included monocyte-derived (CD68+/Mac387+) and pro-fibrotic/anti-inflammatory (CD163+/CD16+) phenotypes. We established that the utility of this platform could be extended to liver biopsies from patients with other chronic liver diseases including nonalcoholic steatohepatitis and autoimmune hepatitis. Each disease exhibited a unique profile after spectral imaging analysis and this platform holds the potential to identify patients predisposed to progressive liver disease based on the macrophage composition. In summary, spectral imaging is a powerful tool that enables analysis of macrophage profiles in different types of chronic liver diseases and has potential to change the manner in which we evaluate liver biopsies leading to more personalized treatment strategies.

pathology↗

bioRxiv2019

First description of the sexual stage of Venturia effusa, causal agent of pecan scab

Venturia effusa, cause of pecan scab, is the most prevalent disease of pecan in the southeastern USA; epidemics of the disease regularly result in economic losses to the pecan industry. Recent characterization of the mating type distribution revealed the frequency of the MAT idiomorphs are in equilibrium at various spatial scales, indicative of regular sexual recombination. However, the occurrence of the sexual stage of V. effusa has never been observed, and the pathogen was previously believed to rely entirely on asexual reproduction. To explore the existence of a sexual cycle, we paired opposite mating types on oatmeal culture media. In initial experiments, cultures were incubated at 24 C for 2 mo for hyphal interactions to occur between mating types and then maintained at 4 C for 4 mo. Immature pseudothecia were initially observed but following exposure to a 12 h photoperiod for 2 weeks at 24 C, asci and ascospores developed. Further experiments explored the effect of time on pseudothecial development with 4 mo at 4 C as the optimal requirement. The results of this study demonstrate the heterothallic nature of V. effusa. Following experiments investigated progeny from a sexual cross of an albino and a wild-type isolate. Evaluation of isolate pigmentation, mating type, and multilocus genotyping of single ascospore progeny provided evidence that recombination occurred within the sexual crosses. The impact of determining the source of the overwintering ascostroma will aid in management decisions to reduce the primary inoculum in the disease cycle.

pathology↗