Biology subjects

Fu, C.

Publications and source records attributed to Fu, C..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

Prediction of cellular morphology change under perturbations with transcriptome-guided diffusion model

Investigating the cell morphology change after perturbations with high-throughput image-based profiling is of growing interest, considering its wide applications in phenotypic drug discovery, including MOA (Mechanism Of Action) prediction, compound bioactivity prediction, and drug repurposing. However, the vast space of chemical and genetic perturbations makes it infeasible to fully explore all the potential perturbations with image-profiling technologies. Consequently, developing a powerful in-silico method to simulate high-fidelity cell morphological response under perturbations can reduce the experiment costs and accelerate drug discovery. Motivated by this, we proposed MorphDiff, a transcriptome-guided latent diffusion model for accurately predicting the cell morphology response to perturbations. We applied MorphDiff to two large-scale datasets, including one drug perturbation and one genetic perturbation cell morphology dataset covering thousands of diverse perturbations. Extensive benchmarking and comparison with baseline methods show the remarkable accuracy and fidelity of MorphDiff in predicting cell morphological changes under unseen perturbations. Furthermore, we explored the utilities of MorphDiff in identifying and retrieving the MOAs of drugs, which is a crucial application in phenotypic drug discovery. With the designed pipeline for MOA retrieval, we demonstrated MorphDiffs capability to boost the retrieval of the drugs MOAs (Mechanism Of Actions) by generating realistic cell morphology profiles. The average MOA retrieval accuracy of MorphDiff-generated morphology is comparable with that of the ground truth cell morphology, and consistently outperforms the baseline method and gene expressionbased retrieval by 29.1% and 9.7% respectively. We also validated that complementary information provided by cell morphology generated by MorphDiff can help discover drugs with dissimilar structures but the same MOAs. In summary, with its strong capabilities in generating high-fidelity cell morphology on unseen perturbations, we envision MorphDiff as a powerful tool in phenotypic drug discovery by accelerating the phenotypic screening of vast perturbation space and improving MOA identification.

cell biology↗

bioRxiv2025

Spatio-temporal mass spectrometry in living cells reveals regulators of cuproptosis

Cuproptosis is a unique form of regulated cell death triggered by excessive copper accumulation in mitochondria. To decipher the mechanisms of cuproptosis, we develop Spatio-Temporal Mass Spectrometry (STMS) technique to characterize dynamic subcellular proteomic changes during its early stage. STMS analysis reveals distinct subcellular proteome alterations and unique trafficking patterns over time. Through a genetic functional screen, we discover that copper stress reduces OXA1L in mitochondria, disrupting MRPL20 import and impairing oxidative phosphorylation complex I synthesis. This mitochondrial dysfunction promotes MRPL20 nuclear translocation, triggering the mitochondrial unfolded protein response as an adaptive mechanism to restore mitochondrial proteostasis during early cuproptosis. Meanwhile, AMPK phosphorylates ISCU at serine 29, stabilizing ISCU protein, and increasing the abundance of Fe-S cluster-containing proteins, which, in turn, enhances cells susceptible to cuproptosis. Building on this mechanistic insight, we develop AMPK-SPARK, a phase separation-based EGFP reporter for real-time visualization of endogenous AMPK activity in living cells during cuproptosis. Additionally, we identify COMMD4 as a cuproptosis sensor and establish a GFP-tagged COMMD4 cell model for high-content drug screening. Using this platform, we identify three FDA-approved drugs including Plerixafor, Dithranol, and Bleomycin as potential cuproptosis inhibitors. Overall, our work advances the understanding of cuproptosis regulation and provides valuable molecular tools and data resource for future research in this area.

cell biology↗

bioRxiv2025

Three-dimensional tissue platform co-laid with native collagen fibers and cells for phenotypic screening of stem cell interactions

Phenotypic screening of cell-cell and cell-matrix interactions is critical yet challenging for drug discovery and disease modeling. In this study, a scalable 3D tissue platform was developed by co-laying extracted natural insoluble collagen fibers, mesenchymal stem cells, endothelial cells, and neural progenitor cells for phenotypic screening. Cell growth and interactions were enhanced in the co-laid platform, evident through increased cell proliferation, viability, and vascularization. Dense vascular networks rapidly formed through cell-cell and cell-matrix interactions without adding a traditionally needed growth factor set. Both in vitro and implantation studies confirmed that these blood vessels were of human origin. To evaluate the phenotypic screening of cell-cell and cell-matrix interactions, we propose a phenotype screening prototype for stem cell interactions that utilized multivariate analysis encompassing both cell-cell and cell-matrix interactions and demonstrated its effectiveness to screen vasculature formation and autism spectrum disorder (ASD) models. Using the prototype, we confirmed that collagen crosslinking, ROCK, WNT, and YAP pathways impact vasculogenesis. In addition, ASD donor-derived neural progenitor cells can be distinguished from non-ASD control donor-derived neural progenitor cells.

bioengineering↗

bioRxiv2024

Identification of SMARCA1 as a key regulator for Colorectal Cancer

Emerging evidence indicates that aberrations in the writing, reading, or erasure of chromatin modification codes are pivotal events in various human cancers. In this study, we conducted a systematic investigation of histone modification recognition proteins in a pair of colorectal cancer cell lines, SW480 and SW620. Using chromatin fractionation combined with data-independent acquisition mass spectrometry (DIA-MS), we developed a robust method to identify changes in histone modification recognition proteins during cancer progression. Our analysis revealed 22 proteins that were significantly upregulated and 22 proteins that were significantly downregulated in SW620 cells compared to SW480 cells. Notably, SMARCA1, a member of the ISWI family belonging to ATP-dependent chromatin remodeling complexes, was downregulated in SW620 cells compared to SW480 cells. Its high expression was strongly correlated with poor patient prognosis, aligning with the proposed role of SMARCA1 in promoting colorectal cancer (CRC) metastasis. Furthermore, reduced SMARCA1 expression altered the levels of metastasis-related matrix metalloproteinases (MMPs) in these cells. In conclusion, by systematically profiling histone modification recognition proteins in a matched pair of primary and metastatic CRC cell lines, we identified SMARCA1 as a potential driver of CRC metastasis and a promising therapeutic target for CRC patients.

cancer biology↗

bioRxiv2024

Feathered Icons: Drivers of Global Attention on Bird Species

Greater public support to conservation is needed to help address the global biodiversity crisis. However, human attention towards biodiversity is taxonomically biased, leaving many species neglected and their conservation needs unmet. Here we investigated the drivers of public and scientific interest for 10,509 bird species, measured by Wikipedia pageviews and articles in Web of Knowledge. We then used a quasi-experimental design to test the effect on public interest of published updates to the International Union for the Conservation of Nature (IUCN) Red List of threatened species (N = 479). Public and scientific interest were strongly predicted by species charisma, familiarity, utilization, and Red List category. While threatened species received significantly more attention, IUCN Red List category revisions produced asymmetric public response: uplistings (to categories of higher extinction risk) generated a significant but modest immediate increase in pageviews, while downlistings (to categories of lower risk) showed no detectable effect. The traits that predicted responsiveness, genuineness of change (real biological shifts rather than improved knowledge or revised taxonomy) and increasing population trend, differed from those driving underlying interest. These findings underscore the need to raise the profile of species lacking the charismatic or familiar traits that typically attract public and scientific interest.

ecology↗

bioRxiv2024

Adaptation of the tetracycline-repressible system for modulating the expression of essential genes in Cryptococcus neoformans

The opportunistic human fungal pathogen Cryptococcus neoformans has an enormous impact on human health as the causative agent of cryptococcal meningitis, an AIDS-defining illness that results in significant human mortality. To combat C. neoformans infections, there is a dire need to expand our current antifungal arsenal. Essential gene products often serve as ideal targets for antimicrobials, and thus identifying and characterizing essential genes in a pathogen of interest is critical for drug development. Unfortunately, characterization of essential genes in C. neoformans is limited due to its haploid nature and lack of genetic tools for generating effective conditional-expression mutants. To date, the copper-repressible promoter pCTR4 is the mostly widely used system to regulate essential gene expression, however, its expression is leaky and copper has pleiotropic effects. In diverse fungal species, including Saccharomyces cerevisiae, Candida albicans, and Candida auris, the tetracycline-repressible promoter system is a powerful tool to regulate gene expression, however, it has yet to be adapted for C. neoformans. In this study, we successfully implemented the tetracycline-repressible system in C. neoformans to regulate the expression of the essential gene HSP90. Supplementation of cultures with the tetracycline analog doxycycline efficiently depleted HSP90 at both transcript and protein levels and inhibited C. neoformans growth and viability. Thus, this work unveils a novel approach to generate conditional-expression mutants in C. neoformans, providing unprecedented potential to systematically study essential gene function in this important human fungal pathogen.

molecular biology↗

bioRxiv2024

An annotated biobank of triple negative breast cancer patient-derived xenografts featuring treatment-naive and longitudinal samples throughout neoadjuvant chemotherapy

Triple negative breast cancer (TNBC) that fails to respond to neoadjuvant chemotherapy (NACT) can be lethal. Developing effective strategies to eradicate chemoresistant disease requires experimental models that recapitulate the heterogeneity characteristic of TNBC. To that end, we established a biobank of 92 orthotopic patient-derived xenograft (PDX) models of TNBC from the tumors of 75 patients enrolled in the ARTEMIS clinical trial (NCT02276443) at MD Anderson Cancer Center, including 12 longitudinal sets generated from serial patient biopsies collected throughout NACT and from metastatic disease. Models were established from both chemosensitive and chemoresistant tumors, and nearly 30% of PDX models were capable of lung metastasis. Comprehensive molecular profiling demonstrated conservation of genomes and transcriptomes between patient and corresponding PDX tumors, with representation of all major transcriptional subtypes. Transcriptional changes observed in the longitudinal PDX models highlight dysregulation in pathways associated with DNA integrity, extracellular matrix interactions, the ubiquitin-proteasome system, epigenetics, and inflammatory signaling. These alterations reveal a complex network of adaptations associated with chemoresistance. This PDX biobank provides a valuable resource for tackling the most pressing issues facing the clinical management of TNBC, namely chemoresistance and metastasis.

cancer biology↗

bioRxiv2024

MOSAIC: A Pipeline for MicrobiOme Studies Analytical Integration and Correction

Large-scale and consortium microbiome studies have enabled identification of reliable population-level biomedical signals, wherein integration is essential to eliminate unwanted variations between batches or studies and retain biological signals. Many strategies, each with distinct advantages and limitations, have been adapted or developed for microbiome data. The optimal strategy for a given study needs to be determined on a data-specific, case-by-case basis. Here, we develop the first-of-its-kind MicrobiOme Studies Analytical Integration and Correction (MOSAIC) pipeline to enable a convenient, fair, and comprehensive comparison of integration strategies. It includes modules for pre-processing, integration, and evaluation of artifact removal and signal preservation, using metrics relevant to common microbiome analyses, including alpha and beta diversities, disease prediction, and differential abundance analysis. We applied MOSAIC to extensive real-world and simulated data and found that though no single strategy excels in all aspects, yet certain strategies, the ComBat and ConQuR families, perform better overall.

bioinformatics↗

bioRxiv2024

BST2 induces vascular smooth muscle cell plasticity and phenotype switching during cancer progression

BackgroundSmooth muscle cell (SMC) plasticity and phenotypic switching play prominent roles in the pathogenesis of multiple diseases, but their role in tumorigenesis is unknown. We investigated whether and how SMC diversity and plasticity plays a role in tumor angiogenesis and the tumor microenvironment. Methods and ResultsWe use SMC-specific lineage-tracing mouse models and single cell RNA sequencing to observe the phenotypic diversity of SMCs participating in tumor vascularization. We find that a significant proportion of SMCs adopt a phenotype traditionally associated with macrophage-like cells. These cells are transcriptionally similar to resolution phase M2b macrophages, which have been described to have a role in inflammation resolution. Computationally predicted by the ligand-receptor algorithm CellChat, signaling from BST2 on the surface of tumor cells to PIRA2 on SMCs promote this phenotypic transition; in vitro SMC assays demonstrate upregulation of macrophage transcriptional programs, and increased proliferation, migration, and phagocytic ability when exposed to BST2. Knockdown of BST2 in the tumor significantly decreases the transition towards a macrophage-like phenotype, and cells that do transition have a comparatively higher inflammatory signal typically associated with anti-tumor effect. ConclusionAs BST2 is known to be a poor prognostic marker in multiple cancers where it is associated with an M2 macrophage-skewed TME, these studies suggest that phenotypically switched SMCs may have a previously unidentified role in this immunosuppressive milieu. Further translational work is needed to understand how this phenotypic switch could influence the response to anti-cancer agents and if targeted inhibition of SMC plasticity would be therapeutically beneficial.

cancer biology↗

bioRxiv2024

The Cryptococcus neoformans STRIPAK complex controls genome stability, sexual development, and virulence

The eukaryotic serine/threonine protein phosphatase PP2A is a heterotrimeric enzyme composed of a scaffold A subunit, a regulatory B subunit, and a catalytic C subunit. Of the four known B subunits, the B subunit (known as striatin) interacts with the multi-protein striatin-interacting phosphatase and kinase (STRIPAK) complex. Orthologs of STRIPAK components were identified in Cryptococcus neoformans, namely PP2AA/Tpd3, PP2AC/Pph22, PP2AB/Far8, STRIP/Far11, SLMAP/Far9, and Mob3. Structural modeling, protein domain analysis, and detected protein-protein interactions suggest C. neoformans STRIPAK is assembled similarly to the human and fungal orthologs. Here, STRIPAK components Pph22, Far8, and Mob3 were functionally characterized. Whole-genome sequencing revealed that mutations in STRIPAK complex subunits lead to increased segmental and chromosomal aneuploidy, suggesting STRIPAK functions in maintaining genome stability. We demonstrate that PPH22 is a haploinsufficient gene: heterozygous PPH22/pph22{Delta} mutant diploid strains exhibit defects in hyphal growth and sporulation and have a significant fitness disadvantage when grown in competition against a wild-type diploid. Deletion mutants pph22{Delta}, far8{Delta}, and mob3{Delta} exhibit defects in mating and sexual differentiation, including impaired hyphae, basidia, and basidiospore production. Loss of either PPH22 or FAR8 in a haploid background leads to growth defects at 30C, severely reduced growth at elevated temperature, abnormal cell morphology, and impaired virulence. Additionally, pph22{Delta} strains frequently accumulate suppressor mutations that result in overexpression of another putative PP2A catalytic subunit, PPG1. The pph22{Delta} and far8{Delta} mutants are also unable to grow in the presence of the calcineurin inhibitors cyclosporine A or FK506, and thus these mutations are synthetically lethal with loss of calcineurin activity. Conversely, mob3{Delta} mutants display increased thermotolerance, capsule production, and melanization, and are hypervirulent in a murine infection model. Taken together, these findings reveal that the C. neoformans STRIPAK complex plays an important role in genome stability, vegetative growth, sexual development, and virulence in this prominent human fungal pathogen. Author summaryThis study focused on a highly conserved protein signaling complex known as STRIPAK, which is important for various developmental processes in fungi and humans. By investigating the functions of this complex in Cryptococcus neoformans, it was discovered to play crucial roles in maintaining genome stability, sexual development, and pathogenesis. In particular, mutations in the genes encoding two subunits of the STRIPAK complex were found to lead to significant defects, including abnormal growth and cell morphology, compromised stress response, and impaired virulence. Interestingly, mutation of a third STRIPAK complex subunit resulted in hypervirulence, characterized by increased thermotolerance, enhanced production of melanin pigment and polysaccharide capsule, and reduced survival in infected animals. Our findings reveal that the STRIPAK complex is an important regulator of growth and virulence of C. neoformans, highlighting its potential as a target for therapies aimed at combating fungal infections. This work furthers understanding of how the STRIPAK complex functions in Cryptococcus, and also in other organisms including humans, where related protein phosphatase complexes govern key cellular processes.

microbiology↗

bioRxiv2024

APP beta-CTF triggers cell-autonomous synaptic toxicity independent of Abeta

A{beta} is believed to play a significant role in synaptic degeneration observed in Alzheimers disease (AD) and is primarily investigated as a secreted peptide. However, the contribution of intracellular A{beta} or other cleavage products of its precursor protein (APP) to synaptic loss remains uncertain. In this study, we conducted a systematic examination of their cell-autonomous impact using a sparse expression system. Here, these proteins/peptides were overexpressed in a single neuron, surrounded by thousands of untransfected neurons. Surprisingly, we found that APP induced dendritic spine loss only when co-expressed with BACE1. This effect was mediated by {beta}-CTF, a {beta}-cleavage product of APP, through an endosome-related pathway independent of A{beta}. Neuronal expression of {beta}-CTF in mouse brains resulted in defective synaptic transmission and cognitive impairments, even in the absence of amyloid plaques. These findings unveil a {beta}-CTF-initiated mechanism driving synaptic toxicity irrespective of amyloid plaque formation and suggest a potential intervention by inhibiting the endosomal GTPase Rab5.

neuroscience↗

bioRxiv2024

Cancer vaccine attenuates carcinogen induced head and neck cancer with impaired early T cell response

Effective T cell immunotherapy requires understanding antigen-specific T cell development during tumorigenesis and immune surveillance. Here, we aimed to examine the dynamics of antigen-specific T cells from tumor initiation through progression in a tobacco carcinogen mimetic, 4-nitroquinoline-1-oxide (4NQO)-induced head and neck carcinogenesis model utilizing genetically engineered K5CreERT/+/ROSAOVA-GFP/p53fl/fl (KOG) mice. Our findings showed that early ovalbumin (OVA) expression via direct lingual tamoxifen (T) did not impact cancer development and survival, by comparing mice with tongue epithelium expressing OVA (KOG/T/OVA+) to those without OVA (KOG/T/OVA-) controlled by doxycycline. This equivalent tumor growth cannot be attributed to the loss of OVA expression. Intriguingly, although OVA-specific T cells were initially generated in tumor-draining lymph nodes (TDLN), they became undetectable 3 weeks after tamoxifen injection. Moreover, therapeutic anti-PD-1 was unable to restore OVA-specific T cells in TDLN and did not yield anti-tumor activity. Remarkably, OVA synthetic long peptide (SLP) vaccine induced OVA-specific T cells in KOG/T/OVA+ mice, and the combination of SLP vaccine and anti-PD-1 significantly reduced tongue tumor burden and prolonged survival. This study highlights the role of impaired endogenous antigen-specific T cell responses in immune resistance in head and neck cancer and the potential of cancer vaccines to improve outcomes.

cancer biology↗

bioRxiv2024

Aging disrupts the coordination between mRNA and protein expression in mouse and human midbrain

Age-related dopamine (DA) neuron loss is a primary feature of Parkinsons disease. However, it remains unclear whether similar biological processes occur during healthy aging, albeit to a lesser degree. We therefore determined whether midbrain DA neurons degenerate during aging in mice and humans. In mice, we identified no changes in midbrain neuron numbers throughout aging. Despite this, we found age-related decreases in midbrain mRNA expression of tyrosine hydroxylase (Th), the rate limiting enzyme of DA synthesis. Among midbrain glutamatergic cells, we similarly identified age-related declines in vesicular glutamate transporter 2 (Vglut2) mRNA expression. In co-transmitting Th+/Vglut2+ neurons, Th and Vglut2 transcripts decreased with aging. Importantly, striatal Th and Vglut2 protein expression remained unchanged. In translating our findings to humans, we found no midbrain neurodegeneration during aging and identified age-related decreases in TH and VGLUT2 mRNA expression similar to mouse. Unlike mice, we discovered diminished density of striatal TH+ dopaminergic terminals in aged human subjects. However, TH and VGLUT2 protein expression were unchanged in the remaining striatal boutons. Finally, in contrast to Th and Vglut2 mRNA, expression of most ribosomal genes in Th+ neurons was either maintained or even upregulated during aging. This suggests a homeostatic mechanism where age-related declines in transcriptional efficiency are overcome by ongoing ribosomal translation. Overall, we demonstrate species-conserved transcriptional effects of aging in midbrain dopaminergic and glutamatergic neurons that are not accompanied by marked cell death or lower striatal protein expression. This opens the door to novel therapeutic approaches to maintain neurotransmission and bolster neuronal resilience.

neuroscience↗

bioRxiv2024

ctQC improves biological inferences from single cell and spatial transcriptomics data

Quality control (QC) is the first critical step in single cell and spatial data analysis pipelines. QC is particularly important when analysing data from primary human samples, since genuine biological signals can be obscured by debris, perforated cells, cell doublets and ambient RNA released into the "soup" by cell lysis. Consequently, several QC methods for single cell data, employ fixed or data-driven quality thresholds. While these approaches efficiently remove empty droplets, they often retain low-quality cells. Here, we propose cell type-specific QC (ctQC), a stringent, data-driven QC approach that adapts to cell type differences and discards soup and debris. Evaluating single cell RNA-seq data from colorectal tumors, human spleen, and peripheral blood mononuclear cells, we demonstrate that ctQC outperforms existing methods by improving cell type separation in downstream clustering, suppressing cell stress signatures, revealing patient-specific cell states, eliminating artefactual clusters and reducing ambient RNA artifacts. When applied to sequencing-based spatial RNA profiling data (Slide-seq), ctQC improved spatial coherence of cell clusters and consistency with anatomical structures. These results demonstrate that strict, data-driven, cell-type-specific QC is applicable to diverse sample types and substantially improves the quality and reliability of biological inferences from single cell and spatial RNA profiles.

bioinformatics↗

bioRxiv2024

KMAP: Kmer Manifold Approximation and Projection for visualizing DNA sequences

Identifying and illustrating patterns in DNA sequences is a crucial task in various biological data analyses. In this task, patterns are often represented by sets of kmers, the fundamental building blocks of DNA sequences. To visually unveil these patterns, we could project each kmer onto a point in two-dimensional (2D) space. However, this projection poses challenges due to the high-dimensional nature of kmers and their unique mathematical properties. Here, we established a mathematical system to address the peculiarities of the kmer manifold. Leveraging this kmer manifold theory, we developed a statistical method named KMAP for detecting kmer patterns and visualizing them in 2D space. We applied KMAP to three distinct datasets to showcase its utility. KMAP achieved a comparable performance to the classical method MEME, with approximately 90% similarity in motif discovery from HT-SELEX data. In the analysis of H3K27ac ChIP-seq data from Ewing Sarcoma (EWS), we found that BACH1, OTX2 and ERG1 might affect EWS prognosis by binding to promoter and enhancer regions across the genome. We also found that FLI1 bound to the enhancer regions after ETV6 degradation, which showed the competitive binding between ETV6 and FLI1. Moreover, KMAP identified four prevalent patterns in gene editing data of the AAVS1 locus, aligning with findings reported in the literature. These applications underscore that KMAP could be a valuable tool across various biological contexts. KMAP is freely available at: https://github.com/chengl7-lab/kmap.

bioinformatics↗

bioRxiv2024

Targeting GFPT2 to reinvigorate immunotherapy in EGFR-mutated NSCLC

In the evolving field of cancer immunotherapy, EGFR-mutated NSCLC presents a significant challenge, demonstrating marked innate resistance to established treatments. An effective method to counter this resistance remains elusive. Through comprehensive genetic and pharmacological analyses across various models, we have identified glutamine fructose-6-phosphate transaminase 2 (GFPT2) as a key facilitator of immune evasion in EGFR-mutated NSCLC. Mechanistically, under EGFR mutation condition, GFPT2 expression, which is typically low in normal tissues, is highly induced via EGFR/IRE1/Xbp1s signaling axis, leading to a significant increase in intracellular UDP-GlcNAc and consequently, an altered N-glycosylation profile. GFPT2 escalates the expression and glycosylation of PD-L1, PVR and CD276, bolstering their interactions with CD8+T cells, and amplifies CD73 glycosylation, thereby intensifying adenosine-mediated CD8+T cells suppression. These actions collectively reduce tumor cell vulnerability to CD8+T cell-mediated death. Moreover, GFPT2 regulates EGFR glycosylation, which consequentially modulates the EGFR-dependent secretion of CXCL10 and VEGF, thus impeding CD8+T cell infiltration within tumors. We further identified a GFPT2 isoform-specific inhibitor that potentiates PD-1 blockade therapy beyond that of existing strategy, corroborated by results in xenografts and patient-derived organoids. Together, these findings illuminate the promising therapeutic potential of GFPT2 as a metabolic checkpoint, offering an innovative approach to invigorate immunotherapy in NSCLC with EGFR mutations.

cancer biology↗

bioRxiv2023

In vitro antimicrobial mechanism of diacerein and potential to reverse MRSE resistance to β-lactams

Staphylococcus epidermidis is the most common pathogens causing ocular infection. With the increase of drug resistance rate, it poses a new challenge to anti-infection treatment. In this study, we analyzed the drug resistance of S. epidermidis isolated from the eye in the past 5 years to guide empirical antibiotics treatment. Then, the MIC and MBC of diacerein against MRSE were detected, and continuous induced resistance experiments confirmed that MRSE not easily induce resistance to diacerein. In addition, it was observed that diacerein induced MRSE cell lysis, increased membrane permeability and resulted in intracellular ROS accumulation. Diacerein does not have toxic effects to HCEC at effective bacteriostatic concentrations. The results of checkerboard assay indicated that the combination of diacerein and {beta}-lactams had additive effect on MRSE. We also observed that diacerein may reverse MRSE resistance to {beta}-lactam drugs by affecting the active efflux system. In conclusion, our results provide strong evidence for the high therapeutic potential of diacerein against MRSE.

microbiology↗

bioRxiv2023

E-cadherin-dependent phosphorylation of EGFR governs a homeostatic feedback loop controlling intercellular junction viscosity and collective migration modes.

Actomyosin tension has been shown to be a ubiquitous driver of tissue morphogenesis1, 2. The Rho pathway, a prominent regulatory network influencing cortical tension, plays a central role in both tissue reorganisation and cell migration3-6. While viscous dissipation in the actin network is commonly regarded as a constant passive parameter in cell migration in both 2D and 3D contexts, there is limited knowledge concerning the regulation of dissipative forces arising from viscous drag between cells during collective rearrangement. Here, we found that the phosphorylation of Epithelial Growth Factor Receptor (EGFR) downstream of de novo E-cadherin adhesion7, 8 orchestrates a feedback loop, thereby governing intercellular viscosity via the Rac pathway regulating actin dynamics. Our findings highlight how the E-cadherin-dependent EGFR activity controls the migration mode of collective cell movements independently of intercellular tension. Combining molecular cell biology, micropatterning, and in silico simulation, our work suggests the existence of a regulatory loop by which cells can tune junctional actin viscosity, with implications for the phenomenology of morphogenetic movements.

cell biology↗