Biology subjects

Liu, Y.-J.

Publications and source records attributed to Liu, Y.-J..

8 recordsLinked to original sources

bioRxiv2026

Mechanical confinement drives monocyte-to-macrophage differentiation

Cells in vivo experience mechanically diverse microenvironments in which physical confinement is a pervasive but poorly understood regulator of their behavior and fate. Whether and how mechanical confinement governs immune cell differentiation remains unknown. Here, we reveal that a mechanical cue -- long-term confinement is sufficient to drive monocyte-to-macrophage differentiation through a mechanoepigenetic pathway. In vivo, differentiating monocytes exhibited flattened nuclei in the liver capsule, indicative of confinement by surrounding stromal and parenchymal structures. Using a custom cell confiner to recapitulate this confined niche, we found that confinement induces macrophage-like protrusive architectures, enhances motility, and upregulates macrophage-associated genes in RAW264.7 and THP-1 monocyte-lineage cells. Notably, extending this paradigm to primary murine bone-marrow, human umbilical-cord, and tissue-derived hepatic-associated monocytes yielded similar outcomes, thus enhancing phagocytic capacity, directly demonstrating that mechanical confinement can program monocytes into macrophages. Mechanistically, we found that confinement activates KDM6B, leading to H3K27me3 demethylation, which derepresses macrophage-specific transcriptional programs. Pharmacological inhibition of KDM6B with GSK-J4 restored H3K27me3 and blocked macrophage differentiation both in vitro and in vivo. These findings define a KDM6B-H3K27me3 axis that links nuclear mechanics to transcriptional reprogramming, positioning mechanical confinement as a "super-enhancer-like" cue for engineer macrophage function in therapeutic and bioengineering contexts.

cell biology↗

bioRxiv2026

Comparing aperiodic brain activity between eyes open rest and dynamic visual input using magnetoencephalography

Inscapes is a low demand abstract animation used as an alternative to eyes open rest in neuroimaging studies, particularly with pediatric and clinical populations prone to head motion. Although prior work has established that functional connectivity patterns during Inscapes closely resemble those during rest, no study has examined whether the two conditions differ in aperiodic neural activity, a broadband feature of the power spectrum linked to excitation/inhibition balance. Here we used magnetoencephalography (MEG) in 54 healthy adults to compare spectrally parameterised aperiodic and periodic measures between eyes open rest and Inscapes viewing (visual component only, without audio). At the sensor level, both the aperiodic exponent and offset were significantly higher during rest than during Inscapes across widespread frontoparietal and occipital distributions in both magnetometers and gradiometers. Source level analyses at both the parcellation and vertex levels largely supported these patterns. The pericalcarine cortex was a notable exception, where both aperiodic measures were higher during Inscapes than during rest, indicating a regionally specific reversal in primary visual cortex. These results demonstrate that Inscapes and eyes open rest produce distinct aperiodic spectral profiles, indicating that the two conditions are not interchangeable for analyses involving broadband spectral dynamics or excitation/inhibition balance estimation.

neuroscience↗

bioRxiv2023

A time-resolved multi-omics atlas of transcriptional regulation in response to high-altitude hypoxia across whole-body tissues

High-altitude hypoxia acclimatization requires whole-body physiological regulation in highland immigrants, but the underlying genetic mechanism has not been clarified. Here we used sheep as an animal model for plain-to-plateau transplantation. We generated multi-omics data including time-resolved bulk RNA-Seq, ATAC-Seq and single-cell RNA-Seq from multiple tissues as well as phenotypic data from 20 bio-indicators. We characterized transcriptional changes of all genes in each tissue, and examined multi-tissue temporal dynamics and transcriptional interactions among genes. In particular, we identified critical functional genes regulating the short response to hypoxia in each tissue (e.g., PARG in the cerebellum and HMOX1 in the colon). We further identified TAD-constrained cis-regulatory elements, which suppressed the transcriptional activity of most genes under hypoxia. Phenotypic and transcriptional evidence indicated that antenatal hypoxia could improve hypoxia tolerance in offspring. Furthermore, we provided time-series expression data of candidate genes associated with human mountain sickness (e.g., BMPR2) and high-altitude adaptation (e.g., HIF1A). Our study provides valuable resources and insights for future hypoxia-related studies in mammals.

genetics↗

bioRxiv2023

Vaccinia virus induces EMT-like transformation and RhoA-mediated mesenchymal migration

The emerging outbreak of monkeypox is closely associated with the viral infection and spreading, threatening global public health. Virus-induced cell migration facilitates viral transmission. However, high-resolution dynamics and mechanisms underlying this type of cell migration remain unclear. Here, we investigate the motility of cells infected by vaccinia virus (VACV), a close relative of monkeypox, through combining multi-omics analyses and high-resolution live-cell imaging. We find that, upon VACV infection, the epithelial cells undergo EMT-like transformation, during which they lose intercellular junctions and acquire the migratory capacity to promote viral spreading. After transformation, VACV-induced mesenchymal migration is highly dependent on the actin cytoskeleton and RhoA signaling, which is responsible for the depolymerization of robust actin stress fibers, the leading-edge protrusion formation, and the rear-edge recontraction. Our study reveals how poxviruses alter the epithelial phenotype and regulate RhoA signaling to induce fast migration, providing a unique perspective to understand the pathogenesis of poxviruses.

cell biology↗

bioRxiv2022

Microsecond pulse electrical stimulation modulates cell migration

Wound healing is a complicated process for maintaining skin integrity after injury, for which electrical stimulations (ES) are ascribed to promote wound healing by facilitating cell migration. Time-shortening of the stimulation treatment from current hours to minutes for efficient wound healing but free of cell damage in return, is however rather a challenge. Here, a novel mechanism of ultrashort pulse electric field (PEF), microsecond PEF at higher voltage, is proposed and realized to promote wound healing under a much short time (seconds) for the total treatment. We revealed that microsecond PEF regulated actin cytoskeleton reorganization and focal adhesion turnover, promoting fibroblasts migration in 2D cell cultures under the pulse stimulation. This accelerated fibroblast migration was accompanied by the mutual promotion with extracellular matrix (ECM) alignment in 3D microenvironments, which cooperatively benefit the eventual wound healing, and these findings were further confirmed by the enhanced skin wound healing in a classic mouse model. Additionally, we coined an actin- and collagen-dependent mechanism of microsecond PEF-mediated wound healing. The quantitative mechanism proposed here for our novel microsecond pulse electric filed (sPEF) methodology orients the new practical electric treatment in a wide range of biomedical applications, such as wound healing, regenerative medicine, and tissue engineering.

bioengineering↗

bioRxiv2021

mTOR Inhibition Overcomes RSK3-mediated Resistance to BET Inhibitors in Small Cell Lung Cancer

PurposeSCLC is a recalcitrant malignancy with limited treatment options. BET inhibitors have shown promising preclinical activity in SCLC, but their broad sensitivity spectrum limits their clinical prospects in this malignancy. Drug combination could be a solution. Experimental designWe performed high-throughput drug combination screens in SCLC cell lines to identify potential therapeutics synergizing with BET inhibitors. Validation was performed in SCLC cell lines and patient-derived xenograft models. Genome-wide RNA sequencing of xenograft tumors was performed to determine the mechanism underlying the synergy of the drug combination. ResultsInhibitors of the PI-3K-AKT-mTOR pathway were the top candidates from the screens. Among the therapeutics targeting this pathway, mTOR inhibitors showed the highest degree of synergy with BET inhibitors in vitro. Furthermore, the combination of these two classes of drugs showed superior antitumor efficacy and tolerability in vivo. Using both in vitro and in vivo SCLC models, we demonstrate that BET inhibitors activate the intrinsic apoptotic cascade, and mTOR inhibitors further enhance these apoptotic effects. Mechanistically, BET inhibitors activate the TSC2-mTOR-p70S6K1 signaling cascade by upregulating RSK3, an upstream kinase of TSC2. Activation of p70S6K1 leads to BAD phosphorylation and cell survival. mTOR inhibition blocks this survival signaling cascade and potentiates the antitumor effects of BET inhibitors. ConclusionsOur results demonstrate that RSK3 upregulation is a novel resistance mechanism of BET inhibitors in SCLC, and mTOR inhibition can overcome this resistance and enhance apoptosis. These findings provide a rationale to evaluate the combination of mTOR and BET inhibitors in patients with SCLC.

cancer biology↗

bioRxiv2021

Targeting metabolic adaptations in the breast cancer liver metastatic niche using dietary approaches to improve endocrine therapy efficacy

Estrogen receptor-positive (ER+) metastatic tumors contribute to nearly 70% of breast cancer-related deaths. Most patients with ER+ metastatic breast cancer (MBC) undergo treatment with the estrogen receptor antagonist fulvestrant (Fulv) as standard-of-care. Yet, among such patients, metastasis in liver is associated with reduced overall survival compared to other metastasis sites. The factors underlying the reduced responsiveness of liver metastases to ER-targeting agents remain unknown, impeding the development of more effective treatment approaches to improve outcomes for patients with ER+ liver metastases. We therefore evaluated site-specific changes in MBC cells and determined the mechanisms through which the liver metastatic niche specifically influences ER+ tumor metabolism and drug resistance. We characterized ER activity of MBC cells both in vitro, using a novel system of tissue-specific extracellular matrix hydrogels representing the stroma of ER+ tumor metastatic sites (liver, lung and bone), and in vivo, in liver and lung metastasis mouse models. ER+ metastatic liver tumors and MBC cells grown in liver hydrogels displayed upregulated expression of glucose metabolism enzymes in response to Fulv. Furthermore, differential ER activity, but not expression, was detected in liver hydrogels. In vivo, increased glucose metabolism led to increased glycogen deposition in liver metastatic tumors, while a fasting-mimicking diet increased efficacy of Fulv treatment to reduce the metastatic burden. ImplicationsOur findings identify a novel mechanism of endocrine resistance driven by the liver tumor microenvironment. These results may guide the development of dietary strategies to circumvent drug resistance in liver metastasis, with potential applicability in other metastatic diseases.

cancer biology↗

bioRxiv2018

Emergence of mosaic plasmids harboring Tn1546-ermB element in Staphylococcus aureus isolates

Antimicrobial resistance in Staphylococcus aureus is a major problem and the acquisition of resistance genes may occur by horizontal gene transfer (HGT). The transposon, an important means of HGT, is recognized as a mobile genetic element that can integrate in plasmids, replicate and transfer to other strains. We have previously reported a novel structure of the Enterococcus faecium-originated Tn1546-ermB element in S. aureus. The emergence of the Tn1546-like element is an emerging problem that requires continuous monitoring. In the present study, we expand the examination of Tn1546-ermB element to ermB-positive methicillin-susceptible S. aureus (MSSA) (n = 116) and ermB-positive methicillin-resistant S. aureus (MRSA) (n = 253) during a 16-year period, from 2000 to 2015. PCR mapping showed that 10 MSSA and 10 MRSA carried the Tn1546-ermB element. The 10 MSSA belonged to three sequence types (ST), ST7 (n = 6), ST5 (n = 3), and ST59 (n = 1), and the 10 MRSA belonged to two STs, ST188 (n = 8) and ST965 (n = 2). Since only clonal complex 5 (including ST5, ST85, ST231, and ST371) MRSA, ST8 MRSA and ST5 MSSA have been previously reported to carry Tn1546 plasmids, this is the first report describing the presence of the Tn1546-ermB element in ST7/5/59 MSSA and ST188/965 MRSA. Plasmid sequencing revealed that the Tn1546-ermB element was harbored by five different mosaic plasmids. In addition to resistance genes, some plasmids also harbored toxin genes.

microbiology↗